Tardive dyskinesia (TD) can be observed in patients receiving long-term treatment with dopamine receptor blocking agents. As the indications for these agents have expanded, TD is becoming more prevalent. In this activity, an expert reviews TD including risk factors, prevention, and treatment.
Identification and Management of Tardive Dyskinesia
Identification and Management of Tardive Dyskinesia
Welcome to CME on ReachMD. This activity titled: Identification and Management of Tardive Dyskinesia, is provided by Practicing Clinicians Exchange, PCE, and is supported by educational grants from Neurocrine Biosciences Incorporated. Prior to beginning the activity, please be sure to review the faculty and commercial support disclosure statements as well as the learning objectives.
So now I want to jump in to Identification and Management of Tardive Dyskinesia 2022. I'm happy to introduce Dr. Jonathan Meyer, who will start us off today for presenting on tardive dyskinesia. Dr. Meyer is a voluntary Clinical Professor in the Department of Psychiatry at the University of California in San Diego. Welcome Dr. Meyer.
These arehis disclosures. And now we're going to get into a few ARS questions to test your knowledge on this topic as we head into the top. Just make sure that when you get the popup screen, that you select your answer choice, and then make sure to hit ‘submit’ at the bottom of the page so that we can get your answers. Okay. And with that, I'm going to turn it over to Dr. Meyer to take us through the presentation.
Thank you so much, Amber. And here's our learning objectives. We're going to talk about the prevalence of TD in people with schizophrenia, mood disorders, and anxiety disorders. And really emphasizing the fact that TD is an equal opportunity player. As you'll see repeatedly, about half of people with TD have mood and anxiety disorders, like 50%, even though we often think of it as something we see more so in schizophrenia, and we'll talk about how to use the VMAT2 inhibitors and the fact that they are added to existing psychotropic regimens, you don't need to modify the underlying medications used for the patient's psychiatric illness.
So overview, we'll talk about what is TD, its risk factors, prevalence, what we can do to minimize the risk, and then summarize it.
What is tardive dyskinesia? I think most of you kind of know this, but it is clearly a side effect related to typically long-term exposure to dopamine receptor-blocking agents. In our world of psychiatry, these dopamine blockers are antipsychotics. Many of you know there's another drug out there called metoclopramide used for GI motility, which also unfortunately, had dopamine-blocking properties and causes tardive dyskinesia is well. I'm just going to say an antipsychotics for now, but you have to understand there is something else out there.
Yes, antipsychotics were developed for schizophrenia. But in this day and age, maybe 11% of antipsychotic prescriptions in the U.S. for adults is for schizophrenia. We use them for numerous other indications, mostly on label, occasionally off label. And it says the pathophysiology is not well understood. I think we appreciate the fact that part of TD is causing postsynaptic dopamine receptor upregulation, and specifically upregulation of super sensitive D2 receptors. What we don't understand is why in humans, it's persistent. In animal models, it's not. In humans, it tends not to go away.
The hallmark of TD are involuntary movements, but they have a variety of manifestations. The only thing I want to say on this slide, which I think is really important, is that if you have people who remain on antipsychotic therapy, or if they're on mood stabilizers, or both, you may see a lot of movement disorders, which are not tardive dyskinesia. One big difference with TD is that the movements are irregular. If you see somebody with a regular tremor, let's say in their hands or even in their jaw, that is not tardive dyskinesia. Tardive dyskinesia are irregular movements, often jerky, and most importantly, not rhythmic. You can have people with both; we'll see people with drug-induced Parkinsonism and tardive dyskinesia, typically older individuals. But again, if you're looking at somebody and you see rhythmic movements, which are regular, that's not tardive dyskinesia.
Classically, we'll see a lot of it in the head and neck with oral buccal lingual manifestations, tongue protruding, puckering, chewing, grimacing, sometimes tic- like movements with frequent eye blinking, but also you have to look at the whole body; you have to look at the torso, you have to look at the fingers, and you have to look at the toes at least once to make sure that there is nothing there, especially if you're going to be treating somebody with a VMAT2 inhibitor. It’s a movement disorder, but really it is a psychosocial disorder. Because for a lot of people, the manifestations are in the head and neck, and that's what people see first when you go out in public.
There’s a lot of manifestations. As I mentioned, I think really what it comes down to is deciding is this TD or is it not TD? Often the history of dopamine receptor blockade or changes in treatment can be a clue, as well as other manifestations. People with akathisia, it's usually not tardive. Rarely it is. But the only way you’d figure that out is if they were no longer on the antipsychotic, and they still have their complaint. But mostly it's an acute problem related to a recent increase in dose. The same with drug-induced Parkinsonism as well, that we increased the dose and all of a sudden, oh, the patient complains of rigidity, we see the classic Parkinsonian tremor.
Other manifestations really can be tardive dyskinesia. There can be tic-like movement, stereotypies. Sometimes people with their dyskinesia also have dystonia as well. But that box in the center, if it's rhythmic and it's regular, that's not tardive dyskinesia, and requires a different form of treatment.
The standard rating scale most people use is the AIMS. The only thing I really want to say about this is that we only score items 1 through 7 to come up with the quote, AIMS score, which will be used as a monitoring tool, and also to monitor the response to VMAT2 inhibitor treatment. There are other items, 8 through 12, but they are not added together with items 1 through 7. And the reason why it's important to know this is I was recently talking with somebody who had an EHR that was updated recently, and the new one messed up and added up all the items 1 through 12. And they were very frustrated. Make sure if you're using an HER which has the AIMS built in, that it's doing it correctly. If it isn't, then you just have to put in your note, the score from the EHR is wrong, items 1 through 7 add up to whatever it is. How often you do it depends on risk factors. As we'll talk about, one of the biggest risk factors is older age, especially age 65 and above, and also use a first-generation agents. Bare minimum, once a year, with more risk factors at least twice a year, then occasionally even more often.
We used to have these diagnostic criteria, which were invented, as you can see, 40 years ago, to identify TD, and you had to have minimum scores. These days, we don't use this necessarily. I think among the audience which I'm speaking to right now, if you even had a score of 1, and it was in one body part and it was your face, you would want to be treated. People would notice that as they were talking to you and they'd wonder, ‘Do you have gum in your mouth? Are you chewing on something?’ There's no minimum score to diagnose tardive dyskinesia. We do rate severity, of course, but there's no minimum score. Assuming that you think it is TD, and most importantly, the hallmark of TD is persistent. You're not sure if it's TD, if it's really that mild, then look, you just see them again, and see if it is persistent.
Schizophrenia patients sometimes are not aware of their movements, but that's not true for all of them. And simply because the person does not endorse that it’s a problem, does not imply lack of awareness. Yes, some people don't, and that's fine, and I accept that. I work in the world of very sick people; I consult to a state hospital system here in California. Some of these people really are not aware of their movements, but others are, and even if they've come to accept them, unfortunately, or they minimize the impact. Often if you ask them, ‘Do other people notice?’ they may acknowledge, ‘Yeah, other people notice,’ and then you can talk about, ‘Well, how does that make you feel? How does that affect what you want to do? If you take the bus, do people stare at you? If you go to the store, do people notice? Etcetera, etcetera.
Also, even if the patient themselves is maybe on the fence about getting their TD treated, sometimes there are caregivers and family members who really do want the patient to be treated. Often the movements are severe enough that they want to take their loved one out to a meal, out to church, wherever, to some event with the family, but the movements are severe enough that people stare, and they say,
‘You know, we really want to integrate this person into the family activities. We'd like them to go out and do things with us, but the severity of their movements presents a problem.’ And that's often the motivation to get treatment.
Among people who are high functioning enough to post on social media, so already there's a functional level there, nobody likes having tardive dyskinesia. People are angry that they have it. They're frustrated that it’s persistent and how it affects their life. It makes them feel insecure as you can imagine. Again, if you have persistent movements, especially in the head and neck area, people will notice, people will ask questions. And it has a functional component as well. It may interfere with all sorts of activities, depending again, on the severity.
We have the motor impairments on the left here. And again, it does relate to severity to some extent. But also, as I said, it's not just a motor disorder, it really is a functional disorder and the impact on people's lives is quite significant. It really does interfere with them being social, with them being able to do what they want to do as a human being.
Well, what are the risk factors for TD? The biggest one, more than anything, demographically is older age. Female gender is a relative risk factor. The number is debated, but older age absolutely increases your risk at least fourfold, and sometimes fivefold, depending on the study. That doesn't mean we deprive older people of an adjunctive atypical for their treatment-resistant depression, it does mean that we consent people and let them know that the risks exist, but we think the benefit outweighs the risk.
Those people on the lower right who had a lot of sensitivity to D2 blockade are also a greater risk for tardive dyskinesia. Most of that literature comes from the era of first-generation antipsychotics when you had no choice. And that was it. These days, we do see some people who are exquisitely sensitive to D2 blockade but not nearly as much as we used to, because the atypicals have their own built-in mechanism to mitigate movement disorders in the form of serotonin 2A antagonism.
How often does it occur? Well, the bottom line, I think, is worth remembering. If you have a group of people who've never been exposed to a first-generation agent, and only second generation, the prevalence number is 7.2%. That's the best data we have, and this comes from this meta-analysis by Carbon published in 2017; big sample size, 11,000, mostly schizophrenia spectrum disorders. It is what it is; this is the data that we have, when you can send people for an adjunctive atypical for their mood disorder, and they say what's the risk? This is the only number you can give them. It's not 0; is much better than what it was for first-generation agents. As you can see in the middle row, where it says people on current FGA treatments, first generations had a rate of 30%. So more than fourfold greater. That's all you can tell people, the risk isn't 0. And you have to let people know it's out there in the culture now, people have heard the term tardive dyskinesia because of the direct-to-consumer ads. So it does allow you to open up the conversation.
There was a study with exclusively bipolar disorder patients where they found the TD prevalence was around 5%. Most of them were on a second-generation antipsychotic, they'd been on them for a long time. Again, what were the big risk factors, older age, to a lesser extent gender, of course, having the mood disorder itself has often been cited in the literature as a relative risk factor. But among those things, older age is the biggie, as well as being on a first-generation agent.
I alluded to at the beginning, that people with mood disorders are just as much at risk as those with schizophrenia. So this is a great study called the RECONNECT study that looked at prevalence among mood disorders and schizophrenia disorders is almost exactly the same among people with TD. And so if somebody asks you, you know, is there a big difference? You say, no, it's an equal opportunity player, that it's not preferentially in people with schizophrenia, we can see very equivalent rate among those with mood disorders or other psychiatric disorders, really very comparable to those with schizophrenia.
Another way to look at it is it’s another analysis of people with tardive dyskinesia, showing that those with anxiety disorders, I like the term neurotic, you don't see that in slides very often, but that was the terminology because it comes from the ICD code where they brought it from. But look at this, the rates are almost exactly 50% for mood disorders or anxiety disorders, 50% and very similar to what they see in schizophrenia as well, meaning if you take the group of TD patients that now all have schizophrenia, a lot of them will have mood disorder, about 50%, and anxiety disorders. So that mood disorder and, quote, neurotic anxiety disorder number is about 50%. Very similar to what we see with schizophrenia. It doesn't matter what the diagnosis is, what really matters more than anything, is the patient's age and the drug itself.
The highest risk group will be somebody who is naive to an antipsychotic who's been given a first generation with an older age as well. You know, you can see here, the 3-year risk is about 50%. Okay, much, much higher than you would see in this group for a second-generation agent. Eventually it does plateau, and it's not going to go to 100%, but 20% per year for the first few years has been seen in other studies is well. Now don't look at this and say, ‘Well, I have an older person who's been on haloperidol since, you know, the second George Bush was president, he doesn't have TD. Should I take them off his first generation?’ Well, he's probably passed the period of risk. Most people who are going to get it, typically get it within the first 5 years, sometimes it's a little bit longer. If that person has been on that first-generation agent for 30 years and they don't have TD, they're probably not going to get it. And I wouldn't necessarily mess with their underlying antipsychotic for that reason. On the other hand, we don't really have a good reason to start first-generation agents in people at this age. We may use them from time to time, but not as the first treatment.
Second-generation agents, a lot lower. Now, this is an odd study, because a lot of these patients had dementia. And we recognize that they are, even within this age group, at even higher risk because of course they lost a lot of brain plasticity. That being said, they also noted that there was a gender effect, as well, as we'd seen or certainly if they're on a concurrent first-generation agent.
So here's the rates with a second-generation agent. You know, they break it down a little bit versus olanzapine and Risperidone. These numbers are more alike than they are different because there's overlapping confidence intervals. If you want to call it 10% after a couple of years, that's fine. That's a fraction of what it was for a first-generation agent. So again, there's no escaping the fact that there is a risk just by being an older person. Yes, we would say definitely for a new start of an antipsychotic and somebody in this age range, always use a second generation. But there's still risk even there. It's just much, much better than it would be with a first-generation agent.
And these are some subanalyses trying to compare a second and first generation to second generations among themselves. It's a lot of detail. But I think in the end, we would say first generation is severalfold worse than second generation. Second generations are probably more alike than they are different. People try to come up with some subtle differences. I would not hang my hat on that too much. We recognize the one drug which really have virtually no rate of TD is clozapine. The number is essentially zero or very close to it. And in the past before we had VMAT2 inhibitors, people used to switch folks with TD to clozapine just for that reason. In this day and age, that's no longer an evidence-based way to manage tardive dyskinesia. We don't put people on clozapine just to manage their TD. If they have TD, and another reason to go on clozapine, that's fine, but only switch them to clozapine if they have that other reason, usually treatment-resistant schizophrenia, schizophrenia with aggression or suicidality, or schizophrenia with polydipsia.
The other thing that's not evidence based is dose reduction. Dose reduction is not a way to treat tardive dyskinesia, neither is going from a stronger, quote, to a weaker D2 antagonist. That is not the way to treat tardive dyskinesia. And even reversibility is quite low. I mean, yes, if you have somebody with a mood disorder, where you can stop the antipsychotic immediately upon developing TD, that's fine. If they have schizophrenia, you can't do that. And certainly, I encourage you not to do that.
So some further analyses within the SGA group, they felt that aripiprazole looked a little better. Again, I wouldn't hang my hat on that. And believe me, if you talk to the Movement Disorder Neurologists, they tend to see a lot of aripiprazole cases. And there's two reasons for that. Not that it's the hugest offender out there, but who goes to the Movement Disorder Neurologists? It's typically people with insurance, and people's insurance typically are those with mood disorders. And where do we use a lot of aripiprazole? Well, for mood disorders, especially adjunctive unipolar.
All drugs have risk, even quetiapine. We think the risk might not be as high as other agents because it's a weak D2 blocker but there is still risk and if you're going to use it, you still have to consent people for that risk.
Well, how can you, as a humble provider, prevent and treat tardive dyskinesia? Well, preventing means, number one, you use antipsychotics when they need to be used. Obviously, if the person has schizophrenia, they have to be on an agent. Usually, our biggest choice is, number one, let's start with a second generation. But number two, usually try to avoid endocrine and metabolic adverse effects. Sometimes you'll inherit people who are billed as having schizophrenia and you don't think that's correct. Well, that's fine. It's always good to revisit why someone thought that and do they actually even need to be on a D2 blocking agent?
Of course, we always use the lowest maintenance dose possible. We preferentially start everybody in second-generation agents, regardless of its mood or schizophrenia indications. Most importantly, inform people of the risk. As I mentioned before, there's ads out there on TV, many of you may have seen them for both of the VMAT2 inhibitors. I often will say to patients and their caregivers, ‘Have you actually heard the term tardive dyskinesia?’ see what it means to them, and then engage in in discussion.
You don't want to scare people from taking a medicine that will really benefit them. Your job as a clinician is to educate them. ‘I think the benefit outweighs the risk in your case, because you failed a bunch of antidepressants, and I feel like the adjunctive a typical pathway is the way to go. But here's some of the downsides.’ And of course, monitor people regularly using the AIMS, regardless of the indication or the dose.
Well, what are evidence-based treatments? Some of these have small effect sizes. Branched-chain amino acids, I don't think they're even available. But what they did was they interfered with dopamine production just enough to lower that dyskinesia signal. Amantadine is an interesting drug. More and more, we're realizing that we should not be giving people anticholinergic, anti-Parkinsonian medications because of the cognitive impairment. Amantadine is the drug of choice nowadays for drug-induced Parkinsonism. But what's interesting is that anticholinergics, as it says in the bottom of the slide, make TD worse. They treat Parkinsonism, and they make TD worse. Amantadine is kind of interesting, because it treats Parkinsonism, but also makes TD a little bit better. Not a lot, but it certainly doesn't make it worse. Tetrabenazine was developed in the 50s. It's only indication in the U.S. right now is for Huntington's Disease movement, but its mechanism of action is VMAT2 inhibition.
And from that, people develop the two FDA approved drugs for TD. So right now, we only have two FDA approved drugs for TD in the United States, which are valbenazine and deutetrabenazine. But you should recognize that they are derived from tetrabenazine. But only those two have FDA approvals for tardive dyskinesia. Again, VMAT2 inhibitor treatment is the way to go. Most importantly, you don't have to change people's underlying medications. I'll show you some slides on both valbenazine and deutetrabenazine. The proportion of people with severe mental illness in those studies was quite high. And in most of the studies, there was at least 60% schizophrenia patients, none of their antipsychotic was changed. Nothing has to be changed at all. The VMAT2 inhibitor was added. And you'll see the completion rates, they are almost the same as placebo, which really speaks to the tolerability of these newly approved drugs.
So how does a VMAT2 inhibitor work? So what you're seeing is the presynaptic neuron. Okay? The presynaptic neuron takes neurotransmitter from the cytosol and sticks it into the vesicle. So when the neuron is stimulated, those vesicles fuse and release the neurotransmitter into the synaptic cleft. How does neurotransmitter get into the vesicle? It's with VMAT2, vesicular monoamine transporter type 2. We also have a type 1 in our body which is mostly in the periphery. The drugs we use are selective and reversible VMAT2 inhibitors. All we're doing is dialing down that presynaptic dopamine signal just enough to lower the severity of the dyskinesia. These are not disease-modifying drugs. These are symptomatic drugs, but they provide a lot of symptomatic relief.
Here's how deutetrabenazine of valbenazine differ a little bit in terms of what they are delivering. Tetrabenazine itself has complex metabolism, and it very quickly gets metabolized into these dihydrotetrabenazine metabolites, which have different stereo isomers designated as plus or minus alpha and beta. And what we see is that when we take tetrabenazine and look at its metabolites, the plus alpha metabolite actually had the highest affinity for the VMAT2 transporter and the most selectivity as well. So valbenazine really is a pro drug for that plus alpha metabolite, and it gets converted very slowly, which allows you for once-daily dosing. Deutetrabenazine actually gives you the array of metabolites that you would get from tetrabenazine as well. It has different kinetics, which allows it to be dosed twice daily. But for deutetrabenazine, you can see the plus alpha metabolite is a small fraction of what you’d get. The most active of these metabolites at VMAT2 is the plus beta. And that's what's doing all the work for deutetrabenazine is the plus beta metabolite.
Both of these drugs are effective. You should know how to use both of them. Your patient may only have access to one or the other due to insurance reasons. Maybe they didn't like one of the other drugs and they want to try a different one, you have to know how to use both.
Here's some of the basic efficacy data for deutetrabenazine from a flexible-dose study. There's no question that these drugs work. This is a 12-week study. And well tolerated too. So look at the adverse effects. Numerically, they are almost the same as placebo. If you look here, it's very hard to find anything that is at least 2% and more than double the risk of placebo. Very, very well tolerated medication. About the only one really is insomnia using that threshold. And you can see there’s a small signal for akathisia, because we are slowing or moderating presynaptic dopamine release for both the VMAT2 inhibitors, you potentially can overshoot a little bit and give somebody some akathisia. And they also both have warnings for drug-induced Parkinsonism. Not common, but just to reinforce the point of what the mechanism of action is.
But to speak to the tolerability, look at the completion rates in this trial. For placebo 88%, for drug 90%. These are very well tolerated, and these were added to patient's existing psychotropic regimen.
There is a fixed-dose study. The only issue with this study is that they didn't go to the highest dose, which is 48 mg per day. And one point I really want to make is that you must continue to deutetrabenazine titration, because in long-term studies, most people end up on doses of around 39 mg on average. There's no reason to stop the titration sooner unless I guess their AIMS score is 0. Deutetrabenazine requires a bit longer titration than valbenazine, but stick with it. Yes, 24 mg a day is an effective dose, but the fact that people in long-term studies tend to be on mean doses around 39, speaks to the fact that you might want to continue to titration at least get to 36. There's no reason to ever not go below, not get to 36 unless the person has a tolerability issue, which is unlikely but could happen. Then at that point, you can decide if you want to go up all the way to 24 mg twice a day.
General response by AIMS score, you can see at least half the people are getting 30% or more improvement, 1/3 of the people are getting 50% improvement, and some are getting even 70% improvement. Really effective drugs, and again, well tolerated. And well tolerated with response over long periods of time. For those of you who are good at mental math, this is almost a 3-year study. There's two points here. There's no difference when you treat younger or older patients, you can see the change in AIMS score over time is identical whether you're under 55, or 55 and older, and the efficacy is sustained over the years. We actually see this pattern in a number of long-term studies, and it looks like there may be ongoing improvement in the tardive dyskinesia over time. I would not promise that to anybody. What I tell people is we see most of the benefit within those first 6 weeks, which is true. If they see something even more than that over time, that's great, but I would not promise that to them.
CGI is what I, as a clinician, sees. Clinicians see lots of improvement over time. PGI is what the patients see, again, no difference in terms of age that these drugs are equally effective in younger or older patients with schizophrenia.
Adverse effects, again, very well tolerated. Very well tolerated medication, and I think that's important. Yes, tiny, tiny rate of akathisia, but it's not 0. Just remember, if you see it, the easiest response in this case is simply dose reduction; the same if you see some Parkinsonism from the VMAT2 inhibitors.
As I mentioned before, these events started in patients with severe mental illness, just like the ones you're often seeing; 60 to 68% in these two studies have schizophrenia. And look at those completion rates in the far right, almost identical to placebo. And that's really important to remember, you don't have to change people's psychotropic regimen, you simply just add this on, and very well tolerated.
And you get a sense again, that the effect size is at least 0.64 for 24, 0.68 for 36. Unfortunate that we don't have an effect size for 48, but bear in mind, you can go up to 48. I would least go up to 36. Even if people are on a 2D6 inhibitor, where it prevents you from going above 36, that's fine, but everyone should at least get to 36. So keep with the titration.
I already mentioned what valbenazine was designed to do, which was selectively deliver predominantly the one active plus alpha metabolite in which is what it does, and the kinetics are somewhat different, which allows once-daily dosing versus BID dosing for deutetrabenazine. The titration is also pretty short, you start on 40, and after a week, you go to 80. So, again, finish the titration. But this one is a lot shorter. The only reason you would not go to 80 is if the person is on a strong 2D6 or 3A4 for whom 40 mg will be the maximum daily dose. And once again, it works. This is an AIMS change in a fixed-dose 6-week study. You see, not a lot of placebo response here. It's not something that responds to placebo, 40 worked, 80 worked, but 80 works a lot better. The effect size for 80, and I'll show this to you in a subsequent slide, is 0.90. This is about as large as any effect size we have for any drug in psychiatry. We see benefit as early as week 2. I usually try to let people know that it's going to continue to improve at least through week 6. Again, you may see improvement beyond week 6, I wouldn't promise that to patients, but it has been noted in a number of studies.
So this is a very, very busy slide. But you can see from that KINECT 3 fixed-dose trial, what the adverse effects are, and rates are very close to placebo. Look at any event leading to discontinuation of placebo 5.3, drugs 6.0%, very, very small differences. The one thing you might see is somnolence. And I'll show you the aggregate data from all the valbenazine trials. Small rates of akathisia; they're not 0, but they do exist. So just bear in mind that these are possible adverse effects. Remember I said before that you may see improvements after week 6? Well, you might. And this is a 48-week study, you can see ongoing improvement. I don't promise this to patients, but if you see it, they'll think you're the world's greatest clinician.
What happens when you stop the drug? Well, we know TD is largely irreversible, and most people go back to their baseline. You might see a few people who don't. And who are those people? They're usually people who are no longer on an antipsychotic. If they don't go back to baseline, they were just lucky, they may have gone into spontaneous remission while they were on the valbenazine treatment. We don't think these are disease-modifying drugs. If they spontaneously remitted, good for them. But most of your patients, if you stop to the VMAT2 inhibitor, will go right back to their baseline, and then you would start it back up again.
Why would you ever stop it? Well, sometimes you do drive the AIMS score down almost to 0, and the patient says, ‘I don't know if I really need this anymore.’ Fine. Let's stop it. Let's see what happens. We know what mostly will happen. And then we'll just put them right back on.
So these are the CGI, the clinic clinician rated, and PGI, patient rated, and overall AIMS response. Again, the proportion of people who are going to get 50% or more improvement is quite large. These are very effective molecules, and the patients see it, as well as the clinicians.
Long-term open-label study just showing you the ongoing benefit. Again, this is mostly an irreversible disorder. You know, being on a VMAT2 inhibitor is not going to change that. But every once in a while, you might have somebody who's no longer on an antipsychotic, and while they're on their VMAT2 inhibitor, would spontaneously remit, good for them, they're lucky. That's not a common occurrence, though.
The clinician-related scores of normal or not at all showing you there are some people who do get a lot of improvement over time. So it's a way to encourage people to stick with it. Again, I wouldn't promise them that. And the other thing you can notice is the sample sizes drop off quite a bit. So who stays in a study until the end? The people who often get the largest response. It's a little bit of a cherry picking, but that's what happens in open-label studies is you often keep the people who are doing really, really good. So that being said, encourage people to stick with it, they may see improved response over time, although I’d never promised them that.
As I mentioned, the one adverse event which occurred more than 2 times placebo, and at least 2% was somnolence. You may see this. The rule of thumb for valbenazine is if you see somnolence, you just go to the lower dose. Valbenazine now has 3 approved doses, 40, 60, and 80. Standard titration is 40 a week, then you go to 80. If it’s not tolerated, you can go back to 60. If that's still not tolerated, you can go all the way back to 40.
What’s the other things that you might see? Well, again, there is that rate of akathisia. It can happen, and some GI things as well. So it can happen. If people get it, just reduce the dose. We typically do not want to add another medication to treat the Parkinsonism from the VMAT2 inhibitor. We prefer simply dose reduction as the preferred strategy.
Looking at the proportion of people with schizophrenia. Again, 58 to 66% completion rate, almost the same as placebo. Look at KINECT 3, the highest dose, 80, was the most effective, effect size of 0.90. And look at that completion rate, 89%, versus 91% on placebo. That's with 66% of the patients having schizophrenia, being on antipsychotics, and all the other stuff we get people with schizophrenia. Do not change their meds. You don't have to refer people to a Movement Disorder Neurologist to start this, any clinician can do this. This is one of the easiest classes of medications to use in the world of psychiatry.
Again, key features is really kinetic ones. Deutetrabenazine is BID, valbenazine is once a day. Deutetrabenazine still has the package insert taking it with food, which is not necessary for valbenazine. The titration for valbenazine is relatively short, 1 week on 40, then you go to 80. Deutetrabenazine, you start at 6 BID, then you go up by 6 mg per week. Again, I really encourage you to get to 36. The max doses are limited if you're on strong inhibitors. For deutetrabenazine, the max dose is 36 if you’re on a strong 2D6 inhibitor, or valbenazine if it's a strong 2D6 or 3A4 inhibitor, the max dose is 40. And the contraindications are very similar to some extent, but deutetrabenazine did not study it in patients with hepatic impairment, so they can't comment on that. Obviously, you're not going to use deutetrabenazine with another VMAT2 inhibitor or in people on reserpine, which is a non-selective VMAT inhibitor or people on MAOIs.
So again, you know, we like a typical antipsychotics, but they do have a downside. And the downside is because they bind to D2 receptors, there is a risk for TD. We use them, and not to cause movement disorders, but you got to consent people, let them hear the term tardive dyskinesia, make sure they understand what it means. If a person has a mood disorder and they develop some movements early on a treatment, well those are people where you could stop the antipsychotic very early. And potentially there might be reversibility. Rates are typically low. The best data we have is 12%, but that's your best chance of not having it become a permanent condition.
Now, on the other hand, if the person has schizophrenia, we really cannot stop their antipsychotic. Do not switch their antipsychotics to manage their TD, do not reduce their dose to manage TD, and God forbid, do not give them anticholinergics. They do not treat TD, they make it worse, and they cause cognitive impairment. Importantly, use the lowest effective dose and monitor people. Most importantly, we have 2 FDA approved medicines for TD, deutetrabenazine and valbenazine. Know how to use each of them. You don't have to refer people to a neurologist to do this. These are very well tolerated medicines and can be added to the existing psychotropic regimen with no changes in the underlying psychiatric medications.
The titration for these 2 VMAT2 inhibitors is different, and the kinetics are different. You just have to know this, you should know how to use both. Again, you may have people who prefer a longer titration, so for them, maybe deutetrabenazine is fine. Some people are fine with a shorter titration, maybe one didn't tolerate a certain medication, so you have an option, you try the other medication as well. But these are the preferred agents. All the guidelines out there, APA, American Academy of Neurology, given the highest level of evidence, and we're fortunate in this day and age we have 2 FDA approved agents for the treatment of tardive dyskinesia.
At this point, I'm going to hand it back to our host, Amber Hoberg, who's going to take you through the post test.
Thank you so much. And it's such an enlightening presentation on one of my favorite topics, tardive dyskinesia.
So now I want to invite Dr. Meyer back on the screen, and we're going to go through some question-and-answers from the audience. So question number one, does VMAT2 inhibitors have or have not been associated with serum enzyme elevations during therapy?
Not that I know of. That's not something that's typically associated with VMAT2 inhibitor treatment. And of course, they have to check all these things. So there's no requirement that you need to monitor hepatic, let's say, enzymes or things of that sort.
Absolutely. Okay. So second question. This is from Rita. For those working in telepsychiatry, what tips do you have for completing AIMS when nursing support staff is limited?
I think you document, for one thing, the limitation to the exam. You can do an outstanding AIMS if you have a cooperative patient, who can look at the camera, you know, do distracting maneuvers, and then also sit back so you can see both their hands as they're resting between their legs, and have them take off their shoes and socks so you could have them walk. But just document what you're able to do and the limitations thereof. If you can only see the person from the chest above, then document that. If you are not able to get the person to hold the platform steady, just document that. All you can do is the best you can. If you're not able to physically bring the person in for a variety of reasons, just also document that. I think people want to see that you've made a good faith effort to do what you can to try to do a complete examination. And if it's limited, maybe you'll do one part one day when you can see the person, you know, very clearly and at least get this portion of the AIMS. And then perhaps another time when you do have more support, do the rest of it.
Absolutely. And as a provider that does a lot of telepsychiatry this is something that I do on a daily basis, is doing the AIMS. And again, like Dr. Meyer said, you can do a good AIMS, you know, just have to document what you can see. I always say you can see 6 of the 7 items if you have the person hold their hands up. And so really, you know, even in the clinical trials for both these VMAT2 inhibitors, most of the evaluation within, you know, via telepsychiatry, so it definitely is something that can be done, you just have to document those limitations.
Okay, so now Patty has a question. Would these guidelines be appropriate for children? Are any of the FDA approved drugs also approved for children?
Yeah, and actually there's another question later on from Leah about the rate of TD in a pediatric patient. TD is often unseen at all in pre-teens. We really never see it. You never want to say the rate is 0, but it's really close to 0. Maybe because they have so much brain plasticity.
That being said, you still have to monitor them for movement disorders, because kids get akathisia and they get drug-induced Parkinsonism. So you have to monitor that aspect. I think it's not unreasonable, once a year to do some form of an AIMS, even in a preteen just to say, look, I'm paying attention to this issue. I'm not completely ignorant of it, but you will probably never see it.
Unfortunately, if you have somebody under the age of 18 who gets tardive dyskinesia, or that it's really bad luck, these drugs are not yet approved for those under the age of 18. That might be one of the few circumstances where you send them to a Movement Disorder Neurologist and all just to say, sometimes they can do things you and I can't do, using drugs off label, going above the maximum dosages, etcetera, etcetera.
Exactly. Okay. So Yelena has a question. Is there ever a point where you would not start valbenazine due to severity of symptoms, or the symptoms are so chronic, it may not work?
Well, Yelena, in the trials of the VMAT2 inhibitor, so these are the double-blind, placebo-controlled trials, you had people who had TD for 20 and 30 years, it works just as well in them as it does for somebody who's had TD only a few years. Essentially, the TD really is a fixed problem. And don't worry about chronicity, because to be honest, once you've got it, for most people, it will be a chronic problem. It's not going away. It typically also does not progress very much once people get it. You know, they'll progress over a period of time and then that's the way it'll be typically for the rest of their lives. So don't deprive anyone of a VMAT2 inhibitor based either on severity or chronicity.
And to be honest, the more severe it is, the more their needs of the TD treatment with a VMAT2 inhibit because they likely have not only the social problem, but maybe also a functional problem because of the severity of the motor movement. So, really everyone with TD should be offered treatment. If people say no, that's fine, but at least you should document that.
And I would absolutely agree. I mean, the only time I would not use the VMAT2 inhibitors is if this is not a patient that has tardive dyskinesia. And actually practice one of my worst patients with actually a score of 23, which is very significant, you know, when movement and he had wonderful improvement from VMAT2 inhibitors. It actually changed the course of his life. So yes, do not deprive patients of these medications.
Okay, so Jeanette has this question: How does one make a diagnosis of TD in the face of diagnoses which may have the same symptoms either due to their movement disorder diagnosis, or possible side effect of their medication?
Well, as I said, the one thing where people may have trouble differentiating from TD, it's not a psychiatric diagnosis, it's drug-induced Parkinsonism. And often, you can't see people with both in the older age range. But there's usually enough clues that it is tardive dyskinesia, simply because again, the movements will not be rhythmic, they won't be regular, there'll be jerky, and also where you see them as well. We don't see a lot of Parkinsonism in the face. It can happen. You'll see occasionally somebody with a very regular jaw tremor, it's not that common, but the fact that it's rhythmic and regular will give it away. And also, TD is persistent. You know, these aren't just mannerisms in somebody with severe mental illness, you'll see a range of thing which goes beyond what you would think of as simply a mannerism. So time is often your big ally, as well as examination if you have somebody in the office, because people who have Parkinsonism, they have rigidity as well and that'll give it away that this is DIP, as we call it, drug-induced Parkinsonism. But again, movement disorders from antipsychotics that look like Parkinsonism give you a very regular tremor like this. Or if it's from mood stabilizers, it's a very high frequency but regular tremor. There's nothing regular or rhythmic about tardive dyskinesia.
I would totally agree with that. And also look at the timing. When did they start their antipsychotic medications? That's another big clue. You know, tardive meaning late occurring, means most patients are going to be on it for, you know, months to years before they develop it. Drug-induced Parkinsonism tends to come on more acutely. So really, also go back to the timing of when those antipsychotics were started.
Okay, so Jessica has a question. If you take someone off at the VMAT2 inhibitor and have to resume it when their TD returns, do you have to titrate it again?
Okay. Answer, yes. Just follow the standard titration. Yes.
I would agree.
Okay, so, Diana: I have a patient who has abnormal movement, swallowing difficulty, restless legs and arms while sitting and standing, writing notes are affected as well, during the day, but when she goes to sleep, they go away. Could this be a diagnosis of TD?
Yes, all movement disorders go away in sleep, so it's not unique to TD, all movement disorders - there's other movement disorders which arise during sleep, but all movement disorders, Huntington's disease, tardive dyskinesia, Parkinsonism, they all go away while you're asleep.
Absolutely. Okay. So Kinsley: My drug guide mentioned small risk of increase in suicidal ideations as an adverse event with deutetrabenazine. What can you tell us about that?
Yeah, so I think your drug guide needs to be thrown in the trash can and get a different one. The reason I say that is deutetrabenazine has 2 indications. For TD, there is no suicidality warning, neither is there for valbenazine. On the other hand, deutetrabenazine is also approved for Huntington's Disease movement, a very different population, with very high rates of depression, and very high rates of suicide. That suicide warning only applies deutetrabenazine being given to Huntington's disease patients. And if your drug guide did not say that, find a better one, because that's a critical difference. We've never seen a signal when using either of the VMAT2 inhibitors for suicidality or changes in psychiatric symptoms when used for tardive dyskinesia.
Absolutely. And even in the clinical studies, they did do rating scales, looking throughout the clinical studies at this exact manifestation, and all of them are really stable in the TD patients. So I absolutely agree.
Okay, Yasmine asks: In first-generation antipsychotics, we might see TD side effects typically 1 year. For second-generation antipsychotics, when might you notice side effects occurring?
It can still be anytime. There are some people who are uniquely sensitive. The biggest factor more than anything tends to be older age. That often increases the rates and increases the risk. But it could be any time. You might not see it for years and all of a sudden, oh, looks like you got something. And I think that's why, for one thing, you do regular AIMS, but also you educate people, especially if they have a mood disorder, because that's the one patient population where you might be able to abruptly stop the second-generation agent, if you see something that you think is TD and if you're lucky, it will be reversible.
Robin wants to know, in the case that VMAT2 meds are not able to be approved by insurance, can benzodiazepines be used?
Well, we don't like giving benzodiazepines to any human beings these days; they cause cognitive impairment. And there's really no treatment protocol which recommends ongoing benzodiazepine use for almost any disorder out there. They're also not that effective. There was one double-blind, placebo-controlled trial of clonazepam. And it worked for a while, then after 3 to 4 months, it stopped working. So not a strong endorsement.
If I really could not get any of the VMAT2 inhibitors which are FDA approved, I would try to go to generic tetrabenazine. Because it really does work. It’s just you have to titrate it, and the kinetics aren't favorable, you have to give it several times per day. That would be my best alternative. If I couldn't even get that, then I'll go to amantadine.
Totally agree with what you're saying here. But these 2 medications are FDA approved. And now insurance should be covering at least one of these medications, even if that means it has to go through the prior authorization process.
Okay, so Maria wants to know: Can you explain again how TD develops upon reduction of a medication? The example she gave was brexpiprazole. And is the treatment different in this case?
So since we have 1 minute, I'll give you the short sweet answer. TD, this is the postsynaptic neuron, and you have all these upregulated super sensitive receptors. Okay? Every time dopamine hits, we get this exaggerated response. That's what dyskinesia is. Well, if I'm giving an antipsychotic, it doesn't matter what it is brexpiprazole or Haldol, it doesn't matter. While they're on it, it's blocking a certain proportion of these dopamine receptors getting access to dopamine, so we don't see the extent of the TD problem. Sometimes we don't even realize it's there. But we take away the antipsychotic, and all of a sudden, these receptors now have access to all of the dopamine in the synapse. And that's why it transiently may look worse when we stop the antipsychotic. The term for that is withdrawal dyskinesia.
You haven't done anything bad, you've just unmasked the problem that was there. In some instances, if you're lucky, and you don't need to give the antipsychotic anymore, maybe this problem will go away. Often it doesn't, and it's persistent. But that's what is happening right there. You haven't done anything bad to the person, you've just unmasked the severity of the problem.
And last question, because I think this is an important one. And this is from Yasmine. She said you said that anticholinergics can make TD worse, please explain how that happens? And would TD reverse if anticholinergics are stopped?
So anticholinergics restore a certain balance in these neurons in the striatum, because dopamine and acetylcholine have a balance in the neuron. If I give a dopamine blocker and cause Parkinsonism, things become unbalanced. And the way I do that is by blocking some of the acetylcholine signals, so things are now back in balance. Well, in tardive dyskinesia, the problem is excessive dopamine signaling on this neuron because of these upregulated, super sensitive receptors. If anything, what I like to do is actually increase the acetylcholine signal so that things would be back in balance. Now, we can't really do that. The point being is if I give an anticholinergic, I'm actually throwing the system further out of whack. It's the exact opposite of what I'd want to do. If you have someone with TD who is on an anticholinergic, and Amber and I talked about a patient she inherited who had TD and somebody gave them Artane. It's the wrong thing to do, it does make it worse, and you should taper them off. But go slowly, because if you take it away too quickly, people will get rebound effect. The usual taper for an anticholinergic is the equivalent of benztropine, and you can go as slow as 0.5 mg every 2 weeks.
And I totally agree with that. Please do not abruptly discontinue those medicines. It causes more harm sometimes than good for the patient.
Well, thank you so much, Dr. Meyer. This was such a wonderful presentation and good question-and-answer session.
You've been listening to CME on ReachMD. This activity is provided by Practicing Clinicians Exchange, PCE, and is supported by educational grants from Neurocrine Biosciences Incorporated. To receive your free CME credit or to download this activity, go to reachmd.com/CME. Thank you for listening.
All faculty and planners participating in continuing education activities sponsored by Practicing Clinicians Exchange (PCE) are required to disclose all financial relationships with ineligible companies. All relevant conflicts of interest are thoroughly vetted and mitigated according to PCE policy. In addition, all faculty are required to openly disclose any off-label, experimental, or investigational use of drugs or devices discussed in this activity. The faculty and Planning Committee have been advised that this activity must be free from commercial bias and based upon all available scientifically rigorous data from research that conforms to accepted standards of experimental design, data collection, and analysis.
Jonathan M. Meyer, MD, consultant: Alkermes, Intra-Cellular Therapies, Karuna, Neurocrine, Noven, Otsuka America Inc., Sunovion Pharmaceuticals, Teva Pharmaceuticals.
Amber Hoberg, PMHNP, consultant: Acadia, Avanir, BioXcel, Intracellular Therapies, Neurocrine, Teva.
Amanda Zimmerman, PA-C, consultant/advisor/speaker: Averitas; researcher: Collegium.
The planners and content reviewers from Practicing Clinicians Exchange, do not have any relevant financial relationships to disclose except Amber Hoberg, PMHNP and Amanda Zimmerman, PA-C as noted above.
Nps and PAs
After completeing this activity, participants should be able to:
- Identify the relative prevalence of TD in patients with schizophrenia, mood spectrum disorders, and anxiety disorders
- Describe the effective use of VMAT2 inhibitors without discontinuing other essential psychiatric treatments such as antipsychotics and antidepressants
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