Leslie L. Citrome, MD, MPH

 Dr Xavier, any advice for community providers?

 Definitely. The key thing to keep in mind is any type of dopamine-blocking agent can cause tardive dyskinesia [TD] or any type of movement disorder. Regardless of if they’re on an antipsychotic or something like an antiemetic that can increase the risk for these movements, visual assessment for movement disorders is essential when they’re prescribed any agent that increases the risk for tardive dyskinesia movements. Specifically, recognize that we’re using atypical antipsychotic medications to treat something more than just primary psychotic disorders, including mood disorders as an adjunct for a major depressive disorder. This makes it essential to monitor so visual assessment.

I stress the importance of monitoring the patient at every visit just to check in with them, to see if they’re developing it. Early intervention is critical. Even though we talk about tardive dyskinesia in terms of years for the onset, from studies we know that it can be answered, can be from several weeks to years. If it’s identified early, then you can either stop the agent or try something different. But the longer the patient has stayed on antipsychotic medication, and TD has developed several years later, then TD may not be irreversible. The impact on the patient is huge. That’s the most critically critical thing that we need to keep in mind.

Think of going back to your teenage years when you had a zit or an acne and how it affected you. Now you’re living with the condition that’s supposed to make your illness better, but you have an adverse effect. That’s not a small thing. To community providers, don’t think that tardive dyskinesia has vanished or isn’t prevalent anymore. With first-generation antipsychotic medications, we knew it was 30%. For someone who was prescribed first-generation antipsychotic medication and who was on the second generation, the risk was still 21%, but someone who has never been on a first-generation medication, the risk is 7%. Lastly, for children, just with the prescriptions, the antipsychotic prescriptions that we give for children to manage behavioral disorders with autism, or behavioral disorders with intellectual disability, the off-label use is really important. Some studies have been done in children. We know that 9% of children who are prescribed antipsychotic medications have these moments. We don’t talk about those things, but they’re really important. The assessment, the monitoring, the follow-up, the conversation with our patients and our family—that’s the most important thing.

 Thank you. We have to assume that TD exists in our practice. If we look for it, we’ll find it. You’re quite right. We use antipsychotics for a wide range of disorders. They are FDA approved for bipolar disorder and as adjunctive use and major depressive disorder, very common usages. One of the sad things about tardive dyskinesia is that someone may develop it after only a few months of being on a second-generation antipsychotic, and you stop that second-generation antipsychotic. Let’s say they have major depressive disorder, and you can use something else. Well, that TD may not go away. This is 1 of the things about TD that’s so maddening. It won’t go away by itself, and we have to treat it. Thank you for your comments regarding advice to community providers. That’s very helpful.

I want to thank you, Dr Xavier, for this conversation, and I want to thank the audience for their attention. Thank you all for watching 

 program. This has been an excellent discussion, and we hope you found the information valuable to your clinical practice.

Videos

In this custom video series, Rose Mary Xavier, PhD, MS, RN, PMHNP-BC, shares advice that can be helpful to community providers who manage children and adult patients prescribed antipsychotic therapy about screening for involuntary body movements and early signs of tardive dyskinesia.

Prevention and Early Detection of Tardive Dyskinesia

 There are some additional points I’d like to talk about before we finish. Who should get treated? Should it be anyone with any movement? Should it be only those with severe movements? I know we touched on it earlier, but I’d like to end up talking about how we approach the TD [tardive dyskinesia] management. What would be the urgency to treat? Let’s reinforce those points.

 The guidance should come from how it’s affecting the patient. It doesn’t matter if it’s mild vs severe. TD is persistent. It can range in severity from mild to severe, but it does affect the patient’s quality of life and it has a huge psychological impact on the patient. Sometimes clinicians aren’t aligned with what the patients need specifically when it comes to an iatrogenic symptom like an adverse effect of the treatment per se. For example, women like to put makeup on, and it’s very hard if you have even a mild tremor to put on lipstick or eyeliners. How often do our clinicians ask about their self-care and how they feel about themselves and the quality of life they have? It depends on the patient. This conversation is an absolute must. We should be talking to our patients. The blanket rule, visual assessment, every time: If you see TD, go ahead and do the formal structured assessments and talk to the patient, talk to the family members, ask about how it’s affecting their life. We’re treating patients so we can make their life better, and if we’re adding to it, and if that’s not a measure of evaluation, we’re losing and not doing a proper job.

 Thank you for that. It’s not just a matter of assessing the movements and measuring how bad they are on the aims. It’s also assessing the impact these movements have on the person whom you’re working with to recover. Part of the recovery journey is to manage everything, to make their lives better for them. If they have movements, it’s going to be stigmatizing. Other people will notice them, even if the patients themselves aren’t completely aware, little incremental changes can go a long way.

I often find it helpful to mention the American Psychiatric Association guidelines for the treatment of schizophrenia, which were recently revised. It’s available for free online. They talk about the management of drug-induced motor adverse effects. They talk about TD in a way they never had before. The guidelines recommend the use of VMAT2 inhibitors, and that recommendation was unanimous based on the evidence, which was considered very convincing and gave it their highest rating. They suggested that people being treated with antipsychotics should be evaluated periodically. In fact, as often as feasible for abnormal motor adverse effects and formally on a scheduled basis. They also recommend, in the presence of moderate to severe TD, that they be treated with a VMAT2 inhibitor. They also mentioned that those with mild TD can be treated. It depends on the patient’s degree of awareness and also the degree of functional impairments that they may be experiencing.

The door is open to the treatment of tardive dyskinesia, from mild on up, for people who need it, and the treatment guidelines certainly encourage us to do so. Now we have treatments available that work quite well.

In this custom video series, recommendations regarding patient selection and use of VMAT2 inhibitors in patients with tardive dyskinesia based on current clinical guidelines and real-world practice are shared.

Treating Tardive Dyskinesia With a VMAT2 Inhibitor

 Dr Xavier, we do have 2 VMAT2 inhibitors available. What are their names?

 They are very similar, aren’t they? They both produce metabolites that are VMAT2 inhibitors per se, that inhibit the transport of dopamine in neurons. What does that actually do?

 It reduces the dopamine storage because the vesicular monoamine transporters are needed to transport the dopamine from the presynaptic vesicles to the postsynaptic for dopamine action. If there isn’t enough dopamine storage or if valbenazine blocks that, then there’s less dopamine available.

 Dopamine, as it sits around in a cell, doesn’t do much. It has to be packaged in those vesicles. If the VMAT2 protein isn’t available to transport that dopamine into the vesicle when the neuron fires, then there isn’t going to be a lot of dopamine being released. That will reduce the dyskinesias that the patient would experience. That’s the thought in terms of the mechanism of action. We have 2 very similar medicines available. There are different terms of what I call the amenities of care. How often do you give it once a day vs twice a day? Do you have to give with food? How are they metabolized? What are the drug-drug interactions? They differ.

Deutetrabenazine, for example, is twice a day with food, and you dose it according to the patient’s needs. It’s very finely dosed. You have a broad range of how you can use this, and you dose it to the point where you have optimal efficacy and tolerability, which is fairly easy to do. With valbenazine, the number of choices of dosing are more limited. It’s once a day, though, with or without food. So that’s a little easier, but it’s metabolized by not only CYP2D6—both are—but also CYP3A4. That means you need to consider another pathway that could be inhibited or induced and that will alter your decision a little in which medicine you might want to prescribe, or basically how you want to dose it. These are more subtle differences.

The bottom line is that both agents work pretty robustly, and the clinical trials are very encouraging. They tell us that the dyskinesias improved quickly and with effects that are noticeable by 6 weeks. The effects are durable with longer exposures. You have ongoing improvement in the dyskinesias that everybody notices. An important aspect of using VMAT2 inhibitors, though—I want to caution our listeners—is that this is a management tool and not a cure. You stop that VMAT2 inhibitor, but it’s likely that the dyskinesias come back. That’s unfortunate that we don’t have a cure, but at least we have a management tool. In the old days, we tried everything. We switched the antipsychotic. We tried to stop the antipsychotic. We gave other medicines that really didn’t work. Now we have VMAT2 inhibitors. That’s a tremendous advance. Any comments about the VMAT2 inhibitors that perhaps I missed?

In this custom video series, key opinion leaders compare VMAT2 inhibitors available for use to treat patients with tardive dyskinesia.

VMAT2 Inhibitors for Tardive Dyskinesia

 There’s one thing about Cogentin [benztropine] that we didn’t talk about. Yes, we know it is useful for drug-induced Parkinsonism, but not for TD [tardive dyskinesia], but I wonder how many of our listeners realize how bad it is for someone’s cognition and how it can impact memory. Our patients with schizophrenia, for example, already have impaired cognition to begin with, giving them an anticholinergic load that they do not need, benztropine will influence their memory and make life more difficult for them. So I really try to minimize the exposure to benztropine in my patients, and I think about alternatives all the time. I wanted to mention that because we often forget about it. Dr. Xavier, any comments in your experience about anticholinergics and cognition?

 No. I agree with you. Even in my patients, I’m very, very hesitant to use benztropine or any type of anticholinergic medication, but at the same time for acute dystonic reactions, it’s highly effective. Often, we must talk about these two differences too, like for tardive no, but acute movement disorders, like if your dystonic reaction, you can use that. Most of the patients who are on antipsychotic medications, they are not acute cases unless you work in an acute care hospital. As a rule of thumb, I guess in our long-term patients or chronic severely ill patients, I think it makes sense to kind of stay away from any type of anticholinergic medication. Especially given that when we look at the trajectory of cognitive function over the course of years, it tends to get worse and the combined effects of a lot of factors with some mild effects of the medications itself that it is causing some cognitive load, also to the impact of the natural age-related changes and so on. So I agree with you.

 Well, I am glad that you have had the same experiences as I did in that regard. To our audience, we chatted before, and we worked in very similar settings. I used to work in a state hospital system in New York and ran an inpatient unit for many years. It was dedicated to research and evaluation, but we did a lot of treatment. We also conducted clinical trials, including in tardive dyskinesia. These patients were very vulnerable to cognitive impairment associated with medicines that we prescribed pretty much routinely. I also have experienced with the act team as Dr. Xavier does and our local act team sort of community treatment team treats very similar patients to who I treated in the state hospital system, very vulnerable people, and exposing them to more anticholinergic is bad news. Now, you did raise one exception. What if they have an acute dystonic reaction like this? I am imitating an acute dystonia, very painful, neck contracts and they really are in much distress. Benztropine can help with that very effectively. The ultimate solution to this problem is going to be changing that anti-psychotic. It is not going to be giving benztropine forever. One person told me that benztropine is a date, not a marriage. That is one way of looking at it. You are going to use benztropine when you need to, but you are not going to want someone to be on it permanently. In fact, in a continuing medical education program that I give, I made a slide of a bottle of Cogentin with skull and crossbones on it to make this point. That basically it is poison. Poison can be therapeutic when used carefully in small doses for a short period of time, but you do not want to give it long-term high dose. So often I see people being put on prophylactic benztropine even before they have had any kind of movement disorder because this is what we used to do with haloperidol in the old days. It is not necessary with the second-generation antipsychotics. I did want to emphasize that point for listeners.

In this custom video series, Leslie L. Citrome, MD, MPH, and Rose Mary Xavier, PhD, MS, RN, PMHNP-BC, caution against the use of anticholinergic medications for Parkinson’s disease and comment on the use of alternative therapies for appropriate patients.

Anticholinergic Medications and Impaired Cognition

 Dr. Xavier, you pointed out that patients could have both drug-induced Parkinsonism and tardive dyskinesia [TD], which makes it challenging indeed to figure out what to do first. And my own opinion in that regard is drug-induced Parkinsonism is easier to deal with than tardive dyskinesia. With drug-induced Parkinsonism we can do things like lower the dose of the antipsychotic, change the antipsychotic. Let me ask you though, and this is a leading question Dr. Xavier, what about Cogentin [benztropine]? Would that work?

 Well, Cogentin can make it worse if you treat, it’s an anticholinergic. If we use anticholinergic to treat tardive dyskinesia, the symptoms can be worse. It will work for the Parkinsonism symptoms, but it is not going to work for the TD. So you have to, again that goes back to making sure that you’re doing the differential for the type of movement condition. It is important to do the assessment. I just want to add a couple of points about the AIMS [abnormal involuntary movement scale] that you just mentioned though. You are right, it is very easy. Once you do it, it totally takes about 5 minutes. But the two components, like visually observing the patient before you do the test and making sure that the patient is sitting in a form chair with which doesn’t have any sidebar or handles, those things are critically important. But then the question comes, what if you are doing a telepsychiatry visit? Now how do you test for muscle rigidity? Now we know that from studies that have looked at administering AIMS in face-to-face assessment where it says at a telepsychiatry, the interrater reliability was actually very close. It was very similar. There was not much of a difference between raters who did face-to-face versus who observed. But the one thing is the muscle rigidity where the physician or the clinician assessed that, that is not included in the rating. You can skip if you want a televisit. But I think the most important thing if you are doing a televisit is to make sure that you have the network bandwidth. Because if it freezes or slows down and you are looking for a movement condition, then it can be very challenging.

 Telepsychiatry has turned our world upside down, hasn’t it?

 Depending on it far more than we ever did before. Now I remember occasionally I would see patients or talk to them on the phone, only when I had to when they could not make it into the office, and then it became routine for a little while. And assessing for movements can be quite challenging on a little tiny screen on your phone. If you are going to do telepsychiatry and going to assess for motor abnormalities, you need to look at them on a bigger screen. And it’s helpful to have someone there with the patient holding the camera, holding the phone from a distance so you can get a better idea of how they look when they’re sitting, their whole body, how they’re walking, and the ability to record and zoom in on let’s say their face when you’re thinking, did I see something there? It is helpful to go back to the videotape so to speak and look at that face and see if that indeed was an abnormal movement that you detected in the jaw, for example. So it does require a little more preparation, but it is not impossible to do. The clinical trials that were done to develop the VMAT2 inhibitors for, and garnered FDA [Food and Drug Administration] approval, they all employed video ratings as their primary way of assessing the TD. So that meant that there were blinded video raters who were not aware of where the patient was during the clinical trial, what they were randomized to or anything, and they were able to examine them, so to speak, by reviewing a videotape. Now the videotape was done very carefully in a very well-lit studio, and that really optimized the conditions to where you can detect abnormal movements. We do not generally have that capability for our patients when we do telemedicine, but we can certainly improve our game by avoiding just looking at a little tiny phone screen. Now we do miss out on assessing rigidity. But the next best thing is assessing their gait and looking at their arm swing. That is very helpful. The other differentiation between drug-induced Parkinsonism and tardive dyskinesia that can be quite instructive is the timing on when these movements started. Now sometimes you do get this information in someone who is newly started on an antipsychotic, and this is the very first time they are on it, is very good information. If they started having an abnormal movement in the first couple of days, it is not tardive dyskinesia, it’s going to be some other movement disorder, and probably means that you need to switch the antipsychotic to something else. But if it emerges after a year or two, and they did not have any problems before then, we are going to be very suspicious of tardive dyskinesia. If we increase the dose of the antipsychotic, the drug-induced Parkinsonism would get worse, but the TD may get a little better. We have masked the TD to some extent. That can be helpful too in our differential. If we lower the dose of the antipsychotic, the drug-induced Parkinsonism should get better, but the TD may look a little worse. So those are some of the clues that we can get. And you had mentioned earlier, Dr. Xavier, about Cogentin not being helpful, benztropine not being helpful. It can make TD worse. It actually says that in its product label, not for TD. Can make TD worse. But let us say we make that mistake, and that we misjudge someone to havea drug-induced movement disorder that we think is drug-induced Parkinsonism. We give them benztropine and they get worse. Well, it is not the end of the world. We can stop the benztropine and we can think through this problem and think about tardive dyskinesia as the real culprit here. It can be instructive to see this because it can help us in the differential diagnosis.

In this custom video series, experts provide insight into strategies that may be helpful to healthcare professionals who manage patients on antipsychotic therapy to best monitor for signs of tardive dyskinesia, with special considerations regarding telepsychiatry.

Managing Patients on Antipsychotic Therapy

 My question to you Dr. Xavier, how would you monitor someone before and after initiating a VMAT2 inhibitor? What is commonly done in your experience?

 Well once it is prescribed, you also want to know because if someone has parkinsonian-type symptoms or other type of acute or dystonic movement presentations, if you put them on a VMAT2 inhibitor, it can get worse. You also want to monitor the response to the treatment. The other thing is if someone, again before starting any treatment, I think we talked about the importance of assessment. And assessment should include the distribution of movements. For example, where are the movements located? What is the severity of the movements? Once you have done that, it becomes easy to monitor. But for someone who has had a TD [tardive dyskinesia] structured assessment, I know we talked about this earlier, but AIMS [Abnormal Involuntary Movement Scale] is essential. An ongoing assessment is really important. Specifically for VMAT2, I think the most essential thing is to make sure that the movement is not getting worse. And that can offer a differential diagnostic perspective as to: what exactly were you treating? Or did you, and some of these movements are, have so much common characteristics? Some can be complex in presentation. Because we can have patients who have tardive dyskinesia who also have parkinsonian-type tremor. The systemic and the neurological presentations that are common that are seen with patients who have schizophrenia who are at an advanced age, it can be very hard to tease that apart.

 A structured assessment would be very helpful in figuring out what that person has. And we did talk a little bit before we started recording about what structured assessments are out there. And you had mentioned to me that you had worked in Minnesota. And in Minnesota they have developed this instrument called the DISCUS. I forget exactly what that acronym stands for, but it is not really used elsewhere. And you had mentioned that you use the Abnormal Involuntary Movement Scale, the AIMS, and that is pretty much the gold standard. It is used in the clinic. It is also used as an outcome measure in research in the development of medicines for tardive dyskinesia. The AIMS, the Abnormal Involuntary Movement Scale, examination should be familiar to most of our listeners. And if not, you should learn about it. It is a standard structured way to assess for tardive dyskinesia and other movements. And it has specific instructions. It does not take very long to do maybe 5 to 10 minutes. But it does require methodically going over several body parts looking for movements and eliciting them through something called activation maneuvers where we ask patients, for example, to touch their thumb to their fingers as quickly as they can while observing their face, to open their mouth and stick out their tongue to look at the facial dyskinesias. We look at their hands, we look at their feet, and we look at their trunk. We look to see how they walk. And all these abnormal movements that we detect the dyskinesias, we can rate on a scale of 0 to 4. Let me mention that scale for a moment for our listeners. Zero means no movement when you rate a muscle group. One is there is a movement or maybe there is not, I’m really not sure. A two is a movement that we can all agree that we see, but it is not dramatic. A three, is a movement that everyone will notice, you cannot miss it. And a four, you cannot miss it from across the parking lot. So, 0 to 4. And there are 7 muscle groups that are systematically reviewed during an AIMS exam. And there is nothing complicated about it. Four of these muscle groups are actually the face. So different parts of the face including the tongue and the jaw. And then there is one item that rates all the upper extremities. Both arms and both hands. There is an item for both legs and feet. And there is a separate item for the trunk. And that is it. And if you just can see dyskinesias in any of these 7 muscle groups, you rate them from 0 to 4. And that gives you an idea of where the dyskinesias are and how severe they are. The overall severity of the dyskinesia is rated on item 8 of the AIMS. Remember that item 8 global assessment. And it is the highest rating you gave for any of the muscle groups you just looked at. And that gives you a sense of the dyskinesia severity. The other items of the AIMS will tell you the, ask you to rate the patient's distress level and awareness, as well as impairment on function. And there are items also that remind us to ask about their dental status and whether they have dentures. And it sounds complex, but it really is very simple and in one sheet of paper. The instructions though for the AIMS help us figure out, is this tardive dyskinesia, or is this drug-induced Parkinsonism, or is this both? And how can I say that you are wondering, because none of the items that we rate actually rate drug-induced Parkinsonism. Here is where the instruction for the AIMS is important to keep in mind. The instructions tell us to do a whole bunch of other things. It does not take long to do, but it tells us look on how the patient walks. If they have a shuffling gait or reduced arm swing, that means they have some degree of rigidity and perhaps drug-induced Parkinsonism. We do not rate that on the form, we just look for it. And the AIMS instructions tell us to do that. The other thing the AIMS instructions tell us to do is extend and flex the patient’s upper extremities to check for stiffness. And if you see cogwheeling like this, then that makes you think of drug-induced Parkinsonism.

In this custom video series, Leslie L. Citrome, MD, MPH, and Rose Mary Xavier, PhD, MS, RN, PMHNP-BC, reference the Abnormal Involuntary Movement Scale (AIMS) rating scale, used to assess the severity of involuntary movements and help diagnose tardive dyskinesia.