Hello dear colleagues, welcome to this podcast. We're going to be talking about Beyond the Side Effects, Understanding and Addressing Tardive Dyskinesia. Now the focus here is going to be for us healthcare providers to appreciate the persistence and pathophysiology of tardive dyskinesia and how do we distinguish it from common medication side effects? Because as we well know, our antipsychotics, be they typical or atypicals, can cause a variety of movement difficulties that can be easily confused with tardive dyskinesia. So my task today is to look beyond the side effect and understand and address tardive dyskinesia.

Okay, so the big challenge here is that many clinicians do perceive tardive dyskinesia as just another side effect of the medication, rather than what it is, a chronic and very often, in fact, in the majority of patients, an irreversible disorder that requires proactive management from us. So perhaps we should deal with this issue quite directly and head on by stating a few things about tardive dyskinesia, that it is actually quite common. It's in fact also quite commonly missed by us, not because we can't see the patient's abnormal movements on most occasions, it's because we often think of it as a different condition. And the most common incorrect diagnosis we apply to it is often what we in psychiatry often call it EPS. EPS as if EPS is a diagnostic category. EPS has become psychiatry's one of its greatest wastebasket diagnosis. And we will have to be very careful not to apply it incorrectly and injudiciously for obvious reasons, right? Because patients can be misdiagnosed, mistreated, and mistreatment can lead to further problems for the patients at a number of levels.

Let's for a second reestablish what we do know about tardive dyskinesia. So tardive dyskinesia as per DSM-5 is a condition caused by exposure to a dopamine blocking agent, which in your and my specialty typically means exposure to atypicals or typical antipsychotics for a variety of disorders such as schizophrenia, bipolar disorder, unipolar depression, and a whole host of other conditions, including the common use of these medications in cognitive difficulties, in developmental difficulties. So there are a number of patients. In fact, the numbers appear to be in the 700,000 plus individuals in America who have tardive dyskinesia, and only about 15 % of them are thought to have receive the right diagnosis. So the question that naturally follows, we in the healthcare field are so tuned into our patients' needs. Why are we having a difficult time looking beyond the side effect to looking at it more as an often irreversible life-impairing condition? I believe the problem starts at the very beginning from our training.

You and I classically have not received a great deal of training in Tardive dyskinesia in our various professional training schools. If you look at someone my age, I hardly got a single conversation about it in five years of training. So that's problem number one. The problem number two was until quite recently, just about eight, nine some years ago, we did not even have treatment options.

So psychiatry thought, what's the whole point of making a diagnosis if I can't treat it? Well, by now we know that is no longer an issue. But the third is we have not been trained to differentiate the most common erroneous diagnosis that gets applied to tardive dyskinesia, which is of course drug induced Parkinsonism. So we'll be talking about that momentarily.

But if you don't mind, let's just remember that the pathophysiology of drug-induced Parkinsonism and that of tardive dyskinesia are completely different. In fact, they're so different, they can be thought of as the sunrise and the sunset in a day, quite opposite to each other. So tardive dyskinesia is caused by an upregulation of D2 receptors while drug-induced Parkinsonism is caused by the downregulation of those receptors. So the symptoms are very different.

We also know that tardive dyskinesia is a disorder of excess movements, right? Excess movements in muscles that are voluntary in nature. But drug-induced Parkinsonism is the opposite. It's too little. That's why we talk about a shuffling gait, mask-like facies and you can also have a rhythmic tremor with it. There are considerable challenges in not making the right diagnosis and I will highlight two for you in the next couple of minutes. And my goal is really not to blame or obviously shame psychiatry, but to encourage those of us in the world of psychiatry to appreciate that this misdiagnosis or delayed diagnosis comes with huge challenges for our patients. Here's the first challenge.

So let's just play out a scenario. So if I do have a patient with tardive dyskinesia, but I've applied the diagnosis of drug-induced Parkinsonism or quote unquote EPS, then the odds are quite high this patient would receive an anticholinergic agent and of course the classic one is benestropine, right? We use that sadly way too frequently in psychiatry. And when one does that, it in fact not only delays the diagnosis, that would be bad enough, right? But the problem is applying an anticholinergic can in fact make tardive dyskinesia biologically and symptomatically much worse. Yes dear colleagues, indeed that much worse.

So it's not just a matter of gosh, I'll get to the right diagnosis in time. An incorrect diagnosis can lead to profound challenges and the emotional burden. By now, my research and my colleagues' research that you most likely have laid your eyes on has demonstrated one crystal clear fact. The emotional burden, the physical burden, the social burden, the biopsychosocial burden of tardive dyskinesia is substantial, particularly in a population that is already very vulnerable to challenges.

So the task we have, my dear colleagues, is to identify high-risk patients and to look for early warning signs. Let's spend a minute talking about both of these two sections. First of all, who's at high risk? But perhaps the question we could also ask in reverses, who is absolutely not at risk? And that's an easy question to answer because the answer is nobody. In other words, everybody, everybody, no matter what your age, your diagnosis, whatever. If they have received a D2 blocking agent, they could develop tardive dyskinesia. But who's at high risk? And here we do have some information. The female gender, older age, the presence of a mood disorder, and of course, the concurrent or past use of an anticholinergic. All of these collude together to create an increased risk of development of tardive dyskinesia. But I should hasten to add, if you're looking for one group of patients who absolutely don't develop tardive dyskinesia and we don't need to worry about them, I'm afraid that patient has not yet been born.

So we should keep a high index of suspicion with everybody, of course, with certain patients like I've described before, more so of a worry, but we do have to think about everybody. And then finally, let's come to perhaps appreciating how does this task of looking for the right diagnosis ultimately help the patient? Well, here's how it can and does help a patient. Once we have the right diagnosis, we could eliminate medications that are causing the patient to have further challenges.

So for example, an anticholinergic could be gradually tapered and stopped. And of course, an appropriate medication for a patient who has tardive dyskinesia, assuming it's mild, especially if they have impairment, they could then get one of the two FDA approved treatment options for tardive dyskinesia, valbenazine or dutetrabenazine. And needless to say, once someone knows what's wrong with them, it's just easier for them and their family to deal with the challenge.

So in conclusion, as you and I look beyond the side effect and do our very best to understand and address tardive dyskinesia, what we find is understanding the pathophysiology of tardive dyskinesia and distinguishing it from other common medication side effects ultimately leads the patient towards the right diagnosis, the right treatment, and obviously as a result of that, to better quality of life and functionality in life. Well, thank you very much, dear colleagues, for allowing me to talk a little bit about this important topic, and I look forward to talking with you on another topic down the road. Goodbye for now.

Welcome back dear colleagues to a discussion on the topic of the hidden toll of tardive dyskinesia: beyond movement symptoms. I am so looking forward to talking about this issue because in many ways, it's a reflection of my 30 plus year career because I started out not at all appreciating that there was a hidden toll to tardive dyskinesia. All I thought was it was just a movement disorder. So I may be a particularly good person to talk about it because I have seen the folly in my thinking and I am really deeply desirous of correcting it in my own practice.

So the truth is, we healthcare providers often visibly see the motor symptoms that our patients have when they have tardive dyskinesia. But the key to truly understanding and treating tardive dyskinesia is to appreciate that it has far reaching effects that impair our patients functioning at every level. In fact, it goes beyond that.

it also affects their relationships. I'll tell you more about that in a minute. But to really understand that, we must perhaps appreciate topic number one, which is the stigma associated with tardive dyskinesia and its impact on mental health. You may be wondering, stigma from who to whom? And I would say it's at multiple levels.

So psychiatry itself has a stigma against the diagnosis of tardive dyskinesia. This is the truth. Perhaps seven or eight years ago when I was training a group of fellow clinicians on tardive dyskinesia, a colleague of mine, perhaps a couple of years older than me and perhaps a couple of years more experienced than me in the world of psychiatry, said this to me very quietly, very thoughtfully.

He said, Rakesh, I have spent an entire lifetime trying not to find tardive dyskinesia in my practice. And now you're saying I should look for it. And in that statement from our colleague, really, it's a sad commentary on where psychiatry as a specialty has been for the last 40 some years, which is fear of tardive dyskinesia and a desire to look any other way but at it straight in the face. And I was wondering why do we have so much trouble with tardive dyskinesia? And I think the reason was because it's iatrogenic. It's the only disorder in DSM that can only be caused because of a medication prescribed by a healthcare provider like you and I.

So I think there's a special level of guilt we have that we probably won't have if a patient develops a panic disorder or obsessive compulsive disorder. So that's the first level of the stigma that we in psychiatry have towards the diagnosis of tardive dyskinesia. But the other is until recently, we have not had a treatment option for it. And it's human nature when you can't do something about a condition, then the desire maybe subconsciously is to look the other way. Well, that has changed. And as a result, the stigma really should be dispelled. But the other stigma is from patients and the family members towards the diagnosis.

So the stigma is, my goodness, I have enough problems with my bipolar disorder or schizophrenia, you are asking me to deal with one more thing and you are the cause of it? The medications I've been taking that you told me I need, they have caused this condition that could be irreversible? Do you see how this battle of stigma kind of ricochets in the examination room all over the place and therefore talking about it openly, like in many ways you and I are doing, is indeed the right way to go.

Point number two I would like to make, it's the appreciation of the significant physical morbidity that occurs in our patients directly as a result of their tardive dyskinesia. Well, what have we seen? We have seen falls, we have seen dental damage, we have seen TMJ, we have seen patients have diaphragmatic complications because diaphragm is partly a voluntary muscle and it can be affected by tardive dyskinesia, aspiration risk goes up. Tongue biting is a challenge. And as said before, stumbles and falls can be a big problem. These individuals often burn themselves while cooking or cutting, and this risk only increases the risk of falls and orthopedic concerns as the population ages. But it's not just that though, folks. It's not just physical.

Research that my group and others have conducted have clearly and convincingly demonstrated patients with tardive dyskinesia have added psychological burden. What we found, their depression is worse, their hopelessness is worse, their social isolation is worse. They in fact also get ostracized by others. They do in situations of interacting on things such as going to the grocery store or in romantic relationships or even in families, where people don't want to go out in public with you because grandma quote unquote is embarrassing. She moves her mouth, she drops her food, she says words in a funny way. So yeah, biopsychosocial impairment is profound. And as a result, the very topic of this conversation which is looking beyond movement symptoms is unusually important.

Now, let's face the question of who is responsible for addressing the biopsychosocial impact of this disorder? And I think it's you and I. And of course, our patients and their family members, we are a team. As a result, when you and I do assessments on our patients, and let's for a second assume the patient has been correctly diagnosed with tardive dyskinesia, obviously based on an assessment of excessive involuntary movements, right? That is the basis of that diagnosis. The new data compels you and I to look beyond it, to look beyond the movement symptoms and look at the person with the movement symptoms.

Our training in the mental health field, whether we are MDs or DOs or NPs or PAs or non-prescribing clinicians, is to take a biopsychosocial history. You know what? We should do that with tardive dyskinesia too. If we use just the marker of physical movements, we are going to be ignoring more than half of the plight of this patient.

So many patients with tardive dyskinesia, while the excess motoric movements are a genuine problem, it is the psychological and social impact that truly robs the patient of quality of life. There is also no doubt that if we wish to address these psychosocial impairments, we really do have to focus on the physical movements. We do.

And that's why making the right diagnosis, initiating appropriate treatment as soon as it is feasible. And the third point is avoiding treatments that might worsen them. Those three are truly key features of taking care of a patient. So let's in summation, return back to the title of my brief conversation with you.

It is the hidden toll of tardive dyskinesia, but the truth is it's actually not all that hidden. The patient is reporting biological, psychological, and social impact. The toll is heavy. It's just that often my eyes are blind to the toll of psychological and social distress, and it is the call to duty for all of us to look beyond movement symptoms and look at the person with tardive dyskinesia and conduct an interview that you and I are really good at. A full assessment of biological, psychological, and social impact and whatever the impact may be in any of these three disorders, that then becomes the North Star of guiding us towards appropriate. treatment.

Well, dear colleagues, thank you very much for letting me speak to you from my heart. And I really appreciate the opportunity to be able to discuss where I was 30 years ago, where I am today, and where I'm hoping to be tomorrow, which is a clinician who truly appreciates all the hidden tolls that our patients with tardive dyskinesia face and a clinician whose heart is into helping the total patient, not just the movement symptoms. Thank you again and goodbye for now.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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