Research-based Treatment of Tics, OCD, and Depression

In this episode, I had a compelling conversation with Dr. Angie Landeros-Weisenberger, an Associate Research Scientist at the Yale Child Study Center. We discuss the current state of research and the latest breakthroughs in treating tics and co-occurring conditions such as OCD and depression. Dr. Angie's expertise and passion for research left me both inspired and hopeful for what's on the horizon in patient care.

Episode Highlights:
[01:30] - Dr. Angie’s history of research.
[02:39] - Innovative treatments on the horizon.
[06:10] - Exploring genetic mysteries of tics.
[09:37] - Breaking the habit loop.
[13:33] - The future of wearables.
[16:18] - Trichotillomania research and why it’s not a tic disorder.
[18:48] - Gender bias in tic diagnosis.
[20:46] - A lifetime with OCD and tics.
[24:33] - Selective serotonin reuptake inhibitors (SSRIs) treatment for OCD.
[27:09] - Science is not set in stone, changes will occur with more research.
[27:25] - Advances in research of tools, such as ketamine, for treatment-resistant depression.
[31:34] - Very promising things are coming through research and studies.

Links & Resources:
Yale Child Study Center: https://medicine.yale.edu/childstudy/  
New Jersey Center for Tourette Syndrome and Associated Disorders (NJCTS): https://njcts.org/

I want to remind all our listeners that each episode we share is a stepping stone to better understanding the intricate world of Tourette Syndrome and related disorders. If you've enjoyed today's episode, rate us and leave a review. Your feedback not only supports the show but also helps us reach and educate more people like you.

Transcript

Angie  00:00
We think that Tourette's definitely has a genetic composition to it. So we know from studies being done, for example, at Yale, we have a Dr. Fernandez that has been working with the genetics and they've actually been working closely with Rutgers and other groups around the world, actually. So we know that that genetics play a role in Tourette's, and tics in general, his line of work has been focused specifically on rare variants. So looking at people that don't have a family history of Tourette's, and then just suddenly out of the blue, they develop tics, what happened in that particular person that we can kind of pinpoint? And can that rare variants or that difference? Help us understand what is happening and people that do have like a genetic family history.

Michael Leopold  00:53
Welcome to the apptech, brought to you by The New Jersey Center for Tourette syndrome and associated disorders, empowering children and adults through education, advocacy and research by sharing the stories and experiences relevant to the TS community. Welcome back to the optic. Today I have the privilege of speaking with Dr. Anjali Landeros Weisenberger. She's a researcher at the Yale Child Study Center and her eclectic research background spans tics, OCD and depression. Dr. ng to kick things off, could you please share a bit about your story and how your involvement in TIG research began?

Angie  01:33
Of course, I am actually originally from Mexico City. That's where I did my medical training my residency. I got contacted or connected with Yale Child Study Center through Andres Martin. I was helping him translate Donald Cohen chapters for Tourette's and that was kind of like my first view into the Tourette's world through the Child Study Center. Once I finished my residency, I came to Yale to do my fellowship with Dr. Lachman. And so I did my postdoc with Dr. Lachman, specifically looking at research in Tourette Syndrome, OCD, and other comorbid diagnoses, I just fell in love with the population. It's just a wonderful, wonderful group of people to work with.

Michael Leopold  02:17
One of the neat things about your background is that because it does span so many areas, you're in such an interesting see where you can speak to the latest research and each of these areas, tics, OCD, depression, and not only where the best treatments are right now, but what's exciting in the clinical pipeline patients can be looking forward to. So what I figured we could do with this episode is go through each of those ticks, OCD and depression, and talk about the current state of research treatment, best practice, how do we treat each of these conditions and of course, there's not one size fits all treatment for everybody. So we can explore some of where we're seeing the best results when multiple treatment options for each of those. And then also what's exciting that patients can look forward to in the years to come. I figured we can start with tics, our listeners are largely in the Tourette community and allies. Talk to me about the current state of treatment for for ticks. So

Angie  03:13
that's actually very interesting. So for the longest time, as most of your listeners probably know, there really hasn't been much in the way of treatment for tics, we've kind of been stuck in the alpha two agonist and the neuroleptic kind of track, specifically speaking for for psycho farm. We had studies looking at bowel Bandha, Xen and other stuff. And I think right now, the one that we're really excited about is phase three trial that is looking at I call it a coPI. Pam, but I think that's my Mexican background. This particular medication had positive results in the phase two trial. Currently, we're doing phase three trial, we're really excited because it seems to be working really well in just being a selective antagonist of dopamine receptors specifically for D one, D five, but without all the baggage that comes from, for example, the neuroleptics with the weight gain, the trouble of metabolic syndrome and things of that nature, the sedation that comes with that, but it has it has its other issues that we're trying to better understand. But But yeah, it's exciting. Other things that are currently being studied is CBD THC. So cannabinoids endocannabinoids. So currently, at Yale, we are working with the University of Hanover with Dr. Muller, and with a company in Israel, we're going to be looking at a medication that combines Dronabinol and palmitoylethanolamide or P A or P to see if we can again have an effect over the TIC behaviors. So that's another promising one that's coming down. The jury is still out on whether CBD THC actually works for Tourette's but it's definitely Really not off the table? Can

Michael Leopold  05:01
there be medicinal like pharmacological treatments for CI s that don't hit a dopamine don't affect that at all? Or is it the case that pretty much all the leading candidates were saying when it comes to medicinal treatments for Tourette affect dopamine in some way,

Angie  05:17
it's hard to say that something won't affect dopamine because in the end, if you think of the nervous system, one of the things that is so absolutely wonderful our about our nervous system is that it uses the same systems for many different things, instead of inventing the wheel for every single thing that we need to do, it kind of uses the same sequences, the same circuits. And so because of that, that's why I was saying that even when we try to get to different parts of the brain, it indirectly has kind of like a downstream effect on to dopamine. So it will eventually come down to how it's affecting GABA ergic or glutamatergic neurotransmitters in the brain.

Michael Leopold  06:00
All right, I got a big question here. So we're we're gonna take a quick side point, pivot away from the tick, this is my ADHD and action here. Firing a question here. Can you explain like I'm in eighth grade, what some of the the major ideologies, the causes of Tourette are thought to be? Yeah, so

Angie  06:21
we think that Tourette's definitely has a genetic composition to it. So we know from studies being done, for example, that year, we have a Dr. Fernandez, that has been working with the genetics, and they've actually been working closely with Rutgers and other groups around the world, actually. So we know that that genetics play a role in Tourette's, and tics in general, his line of work has been focused specifically on rare variants. So looking at people that don't have a family history of Tourette's, and then just suddenly out of the blue, they develop tics, what happened in that particular person that we can kind of pinpoint, and can that rare variants or that difference, help us understand what is happening and people that do have like a genetic family history. So we know that that's part of it. It's a little bit more complex than just genes. One of the other studies being done at Yale is we're looking at with Fleur of Ocarina, we asked people that have a diagnosis of Tourette if they would give us a little piece of their skin on their, on their arm from that little piece of skin. We created. Well, I'm using the royal way. But Florida, yeah, Flores lab, they created stem cells. And then they take those stem cells kind of like in layman's terms, they put them in a little dish. And they give that dish kind of like a recipe or a soup of specific proteins and that sort of thing, to to try to make the stem cells become specific organoids. In this case, we're looking at basal ganglia. And so we're trying to make little organoids in a petri dish. And by doing that, and following the development of the stem cells into organoids, we can follow the cascade of proteins are the the we can start creating like a list of instructions that the cells start following in order to create a certain cell fate in this case, the basal ganglia. And so by doing that, and then comparing those findings with the genetic findings, and then some of the post mortem studies, we can then start kind of creating a bigger or having a better understanding of what is actually happening. For the longest time it was thought that Tourette's might have a min Dalian distribution, you have a father with Tourette's, you have a mother without Tourette's, and then you have a certain percentage of possibilities that your child will have the Punnett squares we did in school. Yeah, exactly. But the reality is that it doesn't work that way. It's it's much it's much more complicated. And I think it alludes to even a little bit of what we were talking before about how downstream it just seems that it's it's a lot more complicated. This this black box of, of our brain is a lot more complicated. It's not just an isolated line, but it's just interconnected. Outside

Michael Leopold  09:23
of the world of Psychopharmacology, what are some other treatments take management practices, interventions that are used to manage threatened tics,

Angie  09:37
so exposure response or treatment, so it's a behavioral treatment. So there's kind of like these these two lines of thinking there's the CBT, where you have an exposure, you slowly start an exposure and you start kind of building a an ability to react to that exposure. And that's mostly used in in Oh, CD. And in tics, it's mostly almost kind of like the opposite approach where you have the exposure, and instead of trying to develop response to it, gradually, you try to use a group of muscles or a set of muscles, that is opposite of what you would need to perform the movement. So for example, if you have a throat clearing tick, then you're going to teach the person how to, for example, try to hold their breath and push their diaphragm down so that you can't perform that action. And so well, let me take a step back. So one of the absolutely wonderful things about Tourette's, and it's a it's a blessing and a curse, is that they're really good at creating these loops of behavior. So once a loop is created, it's kind of like a like, and I'm gonna date myself, it's kind of like one of those record players and it kind of jokes and kind of goes back into the loop and jumps out and it goes back into the loop. So if you think about it, there's a sensory gating system in your brain, this sensory gating system, what it does is, it pretty much helps you filter out unwanted or unnecessary sensory information. So as I tell the medical students, after a while of sitting down on your chair, you stop thinking about the way that the seat feels on your body, or the way that your pants kind of rub against, or the seams rub against your skin. And you stop thinking about the temperature in the room. And this information just becomes kind of like like fades into the background. That is, thanks to our sensory gating system. What happens with a lot of psychiatric disorders, because it's not unique to to Tourette is that some of those sensory pieces keep coming to our conscious awareness. So for example, you had a cold, and you had kind of like a little scratch in your throat, and you can't stop just pushing that sensation into the back of your conscious awareness, it's kind of present and you feel like you have to clear your throat, then comes this part about where people that have Tourette's are really good at creating routines. And so you start clearing your throat, because you have a stimulus that is creating you to, to have that and then you create a loop a behavioral loop, and then that behavior loop continues even in the absence of that stimuli. And so the idea is that with with that treatment, such as ER t, what you're trying to do is teach the body a different type of behavior that is active to the original behavior. So you're kind of breaking that that loop, because you can't use the same muscles for opposing behaviors at the same time. Is

Michael Leopold  12:55
it an oversimplification to say that the Tourette brain might be better at making habits then? That other I think

Angie  13:01
I think it is an oversimplification. But as we were talking, it's a lot more complex. There's a lot more more issues going on. But I think for lay man's purposes, I think it it makes it graspable kind of like, okay, so this is what's happening. So instead of filtering out some of those, those signals, some of them are kind of making it into my conscious awareness. And I'm creating these habits. And then how do I break these habits?

Michael Leopold  13:27
I want to talk a little bit about these wearable devices that I had been reading about. I know there's a there's a group in the UK that that's been working on developing one to help with with tic reduction. Is that something you can speak to?

Angie  13:40
Yeah, so actually, with Dr. Blocks lab, we have been looking at different wearables, we've been testing them out, not so much in a in a rigorous research way, but just trying to see if they will provide us with the information that we need. So there's been a lot in terms of wearables, I don't think that technology is currently at a place where a wearable will give us generalizable information about ticks. Because ticks can happen anywhere in the body. Sometimes the wearables are limited to just movements, for example. And so it will track some movements, but it won't track vocalizations. So are we talking about them having something more of a wearable that registers brain function, but then there is so much variability in the in the brain? I mean, there isn't like a signature pattern that we're looking for within our brain that we can say, Oh, the tick is happening. How do we how do we tease apart involuntary movements from voluntary movements, repetitive voluntary movements, so I think it's a little bit more complicated than that. What

Michael Leopold  14:48
was the goal of the wearables? Is it just to track my tics, the frequency of them is it like give me biofeedback? Say, Michael, you're checking a lot. You should probably go for a walk or like what what's the goal? there,

Angie  15:00
one of the best examples of where wearables are being used for treatment, for example, is in trichotillomania. So trichotillomania is a disorder where you tend to pull your hair, it can be hair anywhere in your body, it's thought to have two different reasons. So one is that there's a specific hair that feels a certain way. So there's a sensory piece to this, this one white hair that is growing on the top of your forehead, and it just feels different. And because it feels different, you feel like you need to target it. Or there's more of automatic polling. So you don't even realize that you're doing it and you're pulling, for example, at your eyebrows. And so the wearables have been coming into play, for example, in trichotillomania and again, they're still kind of a work in progress. There isn't like a perfect wearable. But some of these wearables then kind of alert you that you're absent mindedly pulling out your eyebrows. For example,

Michael Leopold  15:58
I could see this being so helpful for children that may not recognize that pre monetary urge so and to those who just don't get it, the percentage that they don't experience that more notice it that this could be a way to chew to them. You know about what's going on inside their body. Exactly. Is there a reason why trichotillomania is not classified as a tic disorder?

Angie  16:20
That's actually a very good question. So we actually have a trial that we just started where we're starting to look at patients with trichotillomania we're trichotillomania is kind of like the if you think Tourette's doesn't have treatments, trichotillomania is kind of like the Forgotten child. So the idea or up until now the management of trichotillomania is the use of SSRIs. So selective serotonin reuptake inhibitors. But we know that they don't necessarily work for the trichotillomania per se it works more like for underlying anxiety or underlying depression, but they're not necessarily good for the trichotillomania per se the behavior. It has been put out there that trichotillomania is kind of like the female version of Tourette's. So there is thought to be just like in Tourette's, there's a four to one incidents where there's for every four boys there's one girl with Tourette's, and trichotillomania it's thought to be the other way around for every four girls with trichotillomania there's one boy with trichotillomania. But in reality is I think we know very, very little about trichotillomania, the information that is out there about what the epidemiologic numbers really look like I think are not necessarily true to form because trichotillomania can be easily hidden. Trichotillomania is not something that people talk about openly, especially in females, it causes a lot of distress, because it affects you how you look. And and that can have a direct impact. So how you perceive yourself the way you present, yeah, the way you present yourself. It's highly associated with other body focused repetitive disorders like skin picking. So actually, one of the researchers at Yale Child Study Center is Emily Olson. And she has taken the banner and she's currently doing some wonderful genetic studies looking at families looking at trying to better understand kind of what is up with the genetics of trichotillomania. And in working with her, we decided to start treatment trial. And so we're looking at some of these new medications that have come out. So we're specifically looking at bow benzene, for the treatment of trichotillomania I don't know if it's going to work or not. But that's what the what the research is, is going to be about. That's

Michael Leopold  18:46
exciting to hear about, you know, you had mentioned this statistic of Tourette being seen three to four times more in boys and girls. Are we still saying that I've always wondered if that had more to do with like, if there was any chance of a sampling bias there. You know, boys are the ones that are getting diagnosed more. They're the ones that are rowdy in the classroom. But what are your thoughts on that?

Angie  19:08
It seems to be more present in boys. But again, there does seem to be some sampling bias. And tics can be so ubiquitous. People can have tics and not know that they have tics because they don't even realize that they're ticking. Tourette's kind of have this has this natural history where it presents itself around 567 years of age, it goes up, it has kind of like a worst ever around the time puberty hits. And then it can go one of two ways. And usually there people will say that your tics will disappear, you'll you'll grow up your brain will develop and then your tics will tend to disappear or be almost non existent. Or you will continue having your tics and you can kind of continue in that trajectory. And I know that with a lot of the patients that we've worked with, there's kind of like this, almost like expectation that when when adolescents Comments kind of be like the the make or break moment. And I know that there can be a lot of heartbreak that comes with that. But we've seen, for example, people that have had their tics almost disappear or disappear completely, and then having a stressor later in life around their 40s or 50s. And suddenly the tics come back. So it means that that it might be that it doesn't go away completely. The again, it's kind of like that habit formation doesn't go away completely. It's just better controlled by the frontal by the frontal lobe. And then when your brain is otherwise stressed, it has to pay attention to other things, and then the ticks will come out. Talk

Michael Leopold  20:39
to me about some of the research you've done with OCD and as specifically as it could inform our discussion about treatment options. With

Angie  20:46
OCD, I think one of the key features of where we've been working on, we haven't done that many pharmacological treatment, I think the last one we did for OCD was looking at and acetyl cysteine for OCD. And we did do an adult trial using ketamine for OCD, I think our lab has focused more on one kind of understanding the life the life cycle of obsessive compulsive disorder, kind of trying to understand this natural history of what happens with people that have OCD. So one of the really, really cool things about working at Yale is that it's been around for a really long time. And so there's a group of people that were seeing when they were very, very young, when they first started having symptoms. And this can be ADHD, Tourette's, OCD. And we've had the privilege of following these kids now into adulthood, to see just the natural history, how the diagnoses and the and the natural history of each one of these these disorders has manifested itself. And this is independent of whatever treatments, they've had therapies, life histories. So it's been really, really cool to see. Some of these kids grow up. And now they're the ones having kids, and they're coming back now with their kids kind of like, and so. So it's a really, really nice, and again, I think it's part of my love of the of this particular population, but it's been a wonderful group of people to work with. And part of what we've been looking at is people that have just tics, people that have tics and OCD, people that have tics, OCD, ADHD, people that have had PTSD added on to their their diagnoses, people that have had depression bouts of depression come up during their, their episodes of bouts of worsening of symptoms. One that's been very interesting, looking at females, since we were talking about the male to female ratio, how do hormones interact with the presence or absence of text? We know for a fact that hormones drive a lot of the, of the peaks and valleys that in the manifestation of tics within females, you know, how does that correlate with a male counterpart? For example? How does that even look with OCD? Or how does it look with ADHD? How does it look with depression, et cetera, et cetera? So it's a really wonderful, but it's an it's, again, it's it's not a controlled sample, and that we're not giving them a specific treatment, or we're not giving them a specific therapy. We're just kind of following them as they live their lives to understand what happens to the symptoms, what happens to the disorders. And now that they're having kids, what's happening with their kids.

Michael Leopold  23:33
You can see next generation Yeah, well, what are some trends that we see in people who have both Tourette and OCD over the course of their lifetime? I'm curious, as someone who's looked at so many patients, families that have this, what kinds of trends do we see over the span of someone's life?

Angie  23:50
It's very heterogeneous. So there isn't like a one line or a one story fits everyone. I don't think we have enough data to say, for a fact that if you have Tourette's and you're a female, and you also have OCD, this is what's going to happen. So it hasn't quite panned out that way. We again, it's this black box, and it's it's complicated. Yes, yes. I wish I had a better answer, but I don't know.

Michael Leopold  24:17
No, that's, that's that is the answer. I mean, we just that's where we stand right now. We don't know. You know, there's so much going on here. So when it comes to treatment, I know that with with OCD, like you had mentioned that on the pharmacology side, there's not a whole lot we can do.

Angie  24:31
Actually, obsessive compulsive disorder is one of the few psychiatric disorders that we know we have treatments that actually work. So we know that that SSRIs work for obsessive compulsive disorder. The difference is that for example, for a depressive disorder, we would give a lower usually lower doses work better for for depression. And for OCD, we end up giving higher doses of SSRIs. Now, one of the things that has been found and that the doctor blog published on is we know that if you have a comorbid tic disorder, you are more likely to respond to not only an SSRI, but you an added neuroleptic. So giving treatment to with both neuroleptic and an SSRI patients will respond better to treatment. So you're you're kind of treating both things. That's one of the things we do know that if you have OCD, you'll have some response to SSRIs. But if you have OCD and tics, you will, will respond better to both an SSRI and a neuroleptic in combination? That's

Michael Leopold  25:37
so interesting, how mainstream is that with the knowledge of doctors treating this? Yeah,

Angie  25:43
that's one of the sad, sad state of affairs. So part of what we try to do it in the lab that I work in is we try to look at evidence to see if there is a basis to say, categorically, yes, no, it works. It doesn't or what is the percentage of people that will respond to this versus not a lot of psychiatrist. A lot of pediatricians a lot of doctors out there that are treating these disorders still are taught to treat things from the clinical perspective and kind of like from their clinical experience. And the clinical experience doesn't necessarily match the evidence that exists out there. And it's really difficult to to someone that has been treating OCD and that this has worked for them for their particular patients because of the heterogeneity. It's very hard to then come to them and say, what what you've been doing is all wrong. evidence now shows and that's the thing about science is that it's constantly questioning itself. And it's constantly moving. And it's constantly kind of teaching us new ways of understand things. And sometimes it's kind of like, we get to something and we're like, oh, but why don't we just thinking about that, like 20 years ago. And it's like, yeah, but now we better understand because now we have this technology, or we have this finding, that's one of the things that can be challenging about following the science is that it's not set in stone. And it's going to be changing. And you just kind of have to follow the evidence and not marry yourself to one specific idea. It's going to change. Again, it's heterogeneous. That's

Michael Leopold  27:18
we're learning more Yeah, we can only do better. The final topic would love to discuss with the time we have left is depression. I know you've done some interesting research around treatment, resistant depression, and curious if you could share that briefly with our listeners.

Angie  27:33
So along with the evidence based research that that we've been doing in OCD and Tourette's, one of the things that became quite apparent is that we needed better treatments for for depression. And again, it's kind of like this, this thought that if you have a psychiatric disorder, at some point, you will receive an SSRI or neuroleptic, maybe if you're older, you'll get a benzodiazepine we use the tools we have, we use the tools that we have, we just kind of tailor it. We tried to think that we have all of these tools for all of these different things. So we needed to find better tools for depression, we still do. Yale has been at the forefront of the study of ketamine, for treatment resistant depression, and for suicidality in adults. But there was very, very little evidence out there for adolescents. So we decided along with Dr. Jennifer Dwyer, to start looking and seeing does ketamine work for for treatment resistant depression in adolescents? So like everything, it kind of has to go in the stepwise progression. So first, we need to see, can kids tolerate it? So we start and so maybe for for listeners out there that that haven't caught on to the lingo of the phase one phase two trials, that's pretty much what it is. It's kind of like working in a stepwise progression. So first, let's see how well tolerated is it does it have any effect so one infusion of ketamine versus one infusion of something that kind of behaves like ketamine, but it's not just a placebo, because ketamine has certain effects in the in the body that can easily unblinded, so we needed an active placebo. And that's where kind of using a benzodiazepine as an active control would be in place. And so the first trial that we did back in the was 2015 2017. We started looking at seeing if kids tolerated ketamine, if it made any difference in their depressive symptoms, and we started with the sickest of the patients. So patients that had tried many different things and hadn't quite responded to, to treatment, we could make a case of kind of offering something to them without putting them to more risk. And from there, it has evolved it has So currently we're running an r1. We're looking to see kids that have treatment resistant depression, and now we're running the safety trials. So now we're doing repeated infusions of the ketamine to see if the kids have any long term effects that we should be aware of. We're looking at their cognitive development while they're in the trial. So does ketamine affect the way their brain works? Does it have long term consequences? If I'm if I'm giving a child, ketamine does that have long term consequences in their in their brain development? So that those are kind of the questions that we're asking. So compared to where it's at with adults, I think that with adolescents, which is the population that we're focusing on, we're still kind of trying to get those answers, it takes a lot of trial and error patients coming in. Again, each patient has their own unique set of personal experiences, personal genetics, environmental stuff, and whatever. And so each case has to be taken care of. And again, these are usually these kids are very, very sick or, or have gone through a lot. And so it requires a lot of hand holding, and, and just kind of like taking things slowly and just being very meticulous about what has been done. What hasn't been done. What has been tried hasn't been tried adequately, because you might think that you've already tried an SSRI, but did you actually get to an adequate dose? Things of that nature? So it's, it's yeah, it's, it's, it's another another population that it's, it's a very satisfying population, you feel like you can make a difference in and working with these kids. So yeah,

Michael Leopold  31:25
it'll be interesting to see where that where we're reading what the data shows on that. Any other last minute points that you know, our listeners may want to hear that you're you're dying to get out?

Angie  31:36
Just stay tuned with, with what's happening. There's some very, very promising things coming down the pipeline. And so we wouldn't be able to do any of the work that we do if it weren't for a lot of the families that volunteered to be in our studies. And to them, I am eternally grateful. And so to all of you guys that are out there listening, thank you for being part of the research. Thank you for even considering it. And yep, we're moving in the right direction. So yes, it hasn't gone to, to waste

Michael Leopold  32:02
love to hear it. And to our listeners. Thank you for tuning into this episode of the uptick. Join us again in two Tuesdays from now or next episode. Thank you for listening to the uptick, brought to you by The New Jersey Center for Tourette syndrome and associated disorders, empowering you to stretch the boundaries to live your best life. The NJ center for Tourette syndrome and Associated Disorders NJ CTS, its directors and employees assume no responsibility for the accuracy, completeness, objectivity, or usefulness of the information presented on this podcast. We do not endorse any recommendation or opinion made by any guest nor do we advocate any treatment