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Webinar: Severe Irritability in Youth

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>> HOST: welcome to the webinar Severe Irritability in Youth with Dr. Melissa Brotman. Dr. Brotman is the Director of Neuroscience and Novel Therapeutics in the Emotion and Development branch at the National Institute of Mental Health. Currently, her developmental translational research integrates basic and clinical approaches to the study of mood disorders and irritability in children and adolescents.

>> DR. BROTMAN: Well, thank you so much and thank you all for tuning in today to hear about some of the work I'll be presenting
on severe irritability and youth. So first I just want to let everyone know that all the work I'll be discussing today was supported by the Intramural Research Program of the National Institute of Mental Health and I have no conflicts to disclose. So let's talk by starting about-- talking about a clinical case example.

So we all know the type of children that I work with and see. So we're going to talk about nine-year-old JP who has chronic grouchiness and has had temper problems his whole life. And at age four he was actually asked to leave his preschool because of his behavior and was diagnosed with Attention Deficit Hyperactivity Disorder and put on stimulant medications at that time. Now despite this stimulant treatment, he continued to have chronic grouchiness, grumpiness, and temper outbursts when he was frustrated. And he got frustrated when he was told to do something he didn't want to do like clean his room, start his homework, or go brush his teeth. And these temper outbursts and general crankiness were almost every day at home and at least weekly at school and with teachers. Most of his outbursts were verbal, so things like yelling, screaming, or shouting, but sometimes JB would get physical and stomp away, slam doors, or throw things. And so most recently, at nine years old, he was diagnosed with Disruptive Mood Disregulation Disorder.

So what am I going to talk about today? So taking a step back, with JP in our mind, I want to tell you what our goals are today. First, I'm going to answer the question what is irritability? And how do we define irritability? And how did it present? What does it look like in the clinic? Then I want to talk about why it's important to study irritability. And then I'm going to transition to talking about how we're actually studying irritability here in the Intramural Research Program of the National Institute of Mental Health. And then finally, growing out of that research, I want to talk about some new treatments we're studying to treat severe irritability in youth.

So to address our first question, what is irritability?

Well, we define irritability as an increased proneness to anger relative to same-age peers. That is, they get angry more often. They're more frequently angry and they're more frequently irritable. Moreover, when they are angry, they stay angry for a longer period of time so the duration of that anger and irritability is longer. They don't tend to snap out of it-- of their mood as easily as some of their same-age peers. And finally their threshold or what makes the child angry, irritable, or annoyed is generally lower relative to his or her friends. So what makes this child angry doesn't necessarily elicit that same anger response in his or her same-age peer.

So putting this together, we think of irritability of having two complementary components. There's a behavioral component and an affective or mood component. The behavioral component manifests as outburst or increase in motor activity. That is, the child moves around more and there can be verbal or physical aggression. That is, saying or doing aggressive things. And in addition to these outbursts, the child is generally angry, grumpy, or cranky most of the time.

So I keep using this term temper outburst. What is a temper outburst? So it's a behavioral that is physical or affective that is emotional response to frustration or blocked goal attainment. So first I'm going to give you some examples of temper outburst and then next I'll define blocked goal attainment. So temper outburst can manifest in more mild ways such as snapping, mild arguing, name calling, or yelling and screaming. Or they can be more moderate displays such as verbal threats, physical displays of aggression such as kicking things or breaking belongings, clenching fists or raising an arm as if to hit someone or something. And more severe, such as using an object to harm someone, pushing or kicking someone or even shoving, slapping, or hitting another person. And as I said, this often happens in response to blocked goal attainment.

So what is blocked goal attainment? We said temper outbursts are behavior and affective responses to frustration or blocked goal attainment. So it turns out that children's goals are being blocked all the time. When we tell a child, "It's time to get off the iPad." There's the goal of the child continuing to play the game but we're blocking that goal by saying the child has to stop playing the game or it's time to go brush your teeth. Again, the child will likely have to stop their preferred activity or goal and start doing something less preferred. Or, "Honey, it's time to start doing homework." Again, stopping that preferred activity or goal like game or play in some way to do something that may be less preferred. And these can even be things that naturally occur like, "We're having meatloaf for dinner," when the child wanted pizza all day even though he or she didn't tell you or communicate that. Or "It's time to clean your room." Or the blocked goal is something that can be completely out of your control like some friend can't come over for a playdate after all. Or the soccer game this weekend was canceled due to the weather. And we also can see how this manifests in school when, say, the teacher says, "Okay. It's time for everyone to take out and turn in their homework."

So I've talked about temper outbursts and I've talked about blocked goals. The final piece is the affective or emotional component of irritability. So here, I'm not talking about those specific temper outbursts where the child is acutely angry, but kind of this general level of grouchiness or grumpiness in the child. So these children are often thought of and described as crabby, in an irritable mood. I often hear parents saying the child just woke up feeling off this morning, or the child is grumpy, moody. And parents often say they're walking on eggshells around their child to keep their mood in check and have to approach him or her in just that right way, otherwise, he or she will get really upset or cranky.

So hopefully, I've painted a clear picture of how we envision irritability and see it here in the clinic at NIMH. But why do we need to study it? Well, first, and most importantly, irritability poses a profound public health impact. That is, irritability is, in fact, one of the most common reasons that children are referred for psychiatric evaluation and care. And early irritability is associated with later problems in adulthood, including academic problems, poverty. And early severe irritability, if not treated, is associated with later major depressive disorder and suicidality.

So because of these reasons, in 2013, the Diagnostic and Statistical Manual written by the American Psychiatric Association, which operationalizes all mental disorders, created a specific category for use with chronic and severe irritability. This diagnosis was named Disruptive Mood Dysregulation Disorder.

So what is the definition of Disruptive Mood Dysregulation Disorder? So as we've discussed, we see severe and recurrent temper outbursts and these can be verbal or physical manifestations of aggression towards people or property. And these outbursts are generally out of proportion to the situation at hand and inconsistent with the child's developmental level. But that is what may be appropriate behaviorally for a two, three, or four year old to do that exact same behavior is not appropirate in a 9 or 10-year-old. In addition to this more acute temper outburst, these children tend to be generally and persistently irritable or angry most of the time most days and the mood is pervasive, that is it's present in [multiple?] domain such as home, school, and with friends or peers. I want to highlight that this is not simply a parent-child interaction problem. And along with this, these symptoms are in pairing. As you recall with our case example JP, he was asked to leave his preschool. The parents often structure their activities and [family life?] around their child's outburst and irritability such as not going to certain restaurants or even avoiding leaving the home altogether. This is really influencing the child's everyday life.

The onset is prepubertal that is prior to age 10 although the diagnosis cannot be made during the preschool years before age 6. And during the question and answer session, I'm happy to provide more details as to how we got to those particular age cut-off. And the child must not have had a prior manic or hypomanic episode which I'll talk more about in a moment.

Why did DSM create a new diagnosis for childhood irritability specifically? We know that irritability is present in multiple other diagnoses including: bipolar disorder; major depressive disorder; emotion disregulation deficits are observed in attention deficit hyperactivity disorder; generalized anxiety disorder; separation anxiety disorder particularly when a child has to separate from the primary caregiver there's often manifestations of irritability and aggression; social anxiety disorder prior to some kind of social performance or perceived evaluation; panic disorder; post-traumatic stress disorder; we see irritability in oppositional defiant disorder; conduct disorder; and very commonly in the autism spectrum disorders.

So why did DSM create a separate, new diagnosis with irritability as the primary core symptom target? Well, children like JP who I talked about before who were characterized clinically by chronic irritability and temper outburst did not have a specific category of their own in the DSM and in fact, there was controversy. Chronically irritable children with temper outburst like JP were actually being diagnosed as having bipolar disorder. We know that bipolar disorder in adulthood is characterized by discrete episodes of mania and depression and these episodes are a specific change in the mood from the individual's otherwise baseline normal mood. However, there was a hypothesis that bipolar disorder in youth is not episodic.

Instead, some clinicians and researchers thought that childhood bipolar disorder is characterized by severe, chronic irritability and symptoms of attention deficit hyperactivity disorder, such as intrusiveness, pressured speech, talkativeness, agitation. And you could imagine that this has profound implications for the treatment of youth with severe irritability, the long-term course of the illness and the prognosis, and how prevalent it is because we know that symptoms of ADHD and irritability in children are far more common than discrete episodes of mania and depression as characterized by bipolar disorder in youth.

So we did a series of studies about a decade ago to examine this controversy. And to summarize a large series of studies, first, we looked at diagnoses in the parents of children with classic, episodic bipolar disorder who present with discrete episodes of mania and depression, and we looked at the diagnosis of parents with youth with chronic and severe irritability. We found that clinicians rated classic, episodic bipolar disorder in the parents of youth with classic, episodic bipolar disorder.

However, parents of youth with chronic irritability did not have a higher rate of bipolar disorder than the population at large. And we also followed children over time. So that is, if bipolar disorder presents in children as chronic irritability, then, as these children get older, they should be at increased risk to develop classic, episodic bipolar disorder, and now there have been multiple studies looking at this. And in a recent meta-analysis combining many, many, many studies, just to cut to the chase, we found that early irritability was specifically related to major depressive disorder, and anxiety, and oppositional defiance disorder, and early irritability was not related to later, classic, episodic bipolar disorder. 

Also, we found that irritability in youth is scarily prevalent, with estimates around 3%, which, again, is much higher than the estimates of classic, episodic bipolar disorder in youth. So why do we care? Why does it matter if early irritability is bipolar disorder or not? Well, first, and very profoundly, there are treatment implications. And specifically, there are specific psychological treatment implications, which I'll talk about more in a moment.

But first, let me just recap what I've said so far because I've given you a lot of information. So these are kind of the high-level takeaway points. First, irritability is characterized by behavioral and emotional components. We talked about temper outbursts and general crankiness, grumpiness, and irritability. Second, we learned that early irritability in youth is not a pediatric manifestation of bipolar disorder, and, in fact, early irritability is specifically associated with risk for anxiety disorders, major depressive disorders, and impairment in adulthood. And because early irritability appears to be a distinct clinical entity separate from bipolar disorder, there was a new diagnostic category called disruptive mood dysregulation disorder in the most recent edition of the DSM.

So to take a step back, I've talked about what irritability is, and what it looks like, and when parents and teachers see it, and I've also talked about why I think it's important to study irritability. Now, I'm going to transition to talking about how we're studying irritability here in the intramural research program of NIMH.

So based on the prevalence and public health importance of irritability, we developed a translational model in attempt to understand the neural or brain-based and behavioral correlates or associations with irritability, and we did this to help us guide novel treatment development for these kids. We called it a translational model because we based it in part on evolutionarily-conserved processes in animal work. So clearly, this model has a lot going on. There are lots of circles and lots of arrows. So I'm going to break it apart and we're going to walk through it together.

So in terms of a model, first, I want us to kind of think about what are two main, broad classes of stimuli that organize all behavior across species? And I'll let you think about that for a moment. What are broad classes of stimuli that organize all behavior across species? Well, generally, rewards and threats are two broad classes of stimuli that organisms generally approach or avoid. Organisms approach or go towards rewards and things that they like, and avoid, freeze, or flee from threatening or scary stimuli. And viewed with irritability, we see abnormalities in both reward and threat processing. So going back to that super complicated model, if we really transition to the heart of the model, we see two big boxes and we see associations between irritability and abnormalities in reward and thread processing.

So to unpack that a bit more, just looking at that top box, we see that irritability is associated with abnormalities in reward processing-- specifically, frustration and as we talked about before, responses to blocked goals. Goals are rewards. And the second core aspect of the model is that irritability is associated with abnormalities in threat processing. So how do we measure threat and reward processing in the clinic? So turning first to abhorrent threat processing, we often use face stimuli. We see that youth with irritability have deficit in overall face emotion labeling and they have an interpretation bias. That is, they're more likely to view faces as threatening. And consistent with this, their early visual attention is drawn towards threatening faces. And there are neural deficits in the pre-frontal cortex and amygdala that are associated when irritable children are looking at what they perceive as threatening faces.

Second, we probe reward processing and we specifically examine associations between irritability and attention following acute frustration or blocked goals. So turning first to abhorrent threat processing, we often use face stimuli. Why faces? Well, we know that face emotion labeling is very important. Of course, humans are social beings and face emotion labeling is the process of perceiving and interpreting face emotions. And we know that labeling these emotions is absolutely essential for social interaction and communication. And related to this-- deficits and face emotion labeling are associated with pervasive social and interpersonal problems. So how can we measure this in the clinic? Well, we show youth pictures of faces such as neutral faces as this one here and we ask them, "How afraid are you of this face?" And I want each of you to think for a moment, how afraid are you of this face from one, I'm not at all afraid of this face to five, I'm very afraid of this face. And I want everyone to kind of pick a number in their head right now. Is it a two, is it a three? And now, let me tell you that we've found that relative to typically developing youth, children with high levels of irritability report higher levels of fear of these neutral faces. That is, they are seeing these neutral faces as more threatening and we can also create ambiguous faces by morphing a full, emotional happy face, which you could see on the left, with a full, angry face emotion on the right. And if you look at the images in the middle, are they happy? Are they angry? It's kind of hard to tell. They're simply ambiguous. That being said, when youth are shown these faces one at a time in a randomized order - so not in this particular order - and are given a forced choice - that is, they have to decide whether or not the face is either angry or happy - children are actually able to label these faces as, say, happy. They might label these faces as happy or angry. And if we were to plot this with the X-axis here lining up with the faces above, ordered from 100% happy to 100% angry, and we see here on the Y-axis is the number of angry face responses, you see there's a specific morph at which there's a dramatic shift, that really straight slope line, and that's the change in rating from happy to angry faces. And this is called the balance point, or the morph at which there's a shift in the interpretation from rating it as happy to angry. And, in fact, irritable youth rate ambiguous faces as more angry. So again, here we see on the X-axis, we have morphed from 100% happy to 100% angry with different levels of ambiguity in the middle, and on the Y-axis, we see those proportions of angry judgments. And you see here that in red, that the irritable youth are shifted to the left, such that they're seeing these same ambiguous faces as angry. So the question is, how can we leverage this knowledge to generate more effective treatments for these youth? And that's actually exactly what we're doing now. So at first, we assess the baseline balance point, which is that arrow in blue, which, again, is that point at which the child switches from rating the face from happy to angry. But now, we provide correct and incorrect feedback to move their balance point to rate those ambiguous faces which they previously rated as angry as more positive or happy.

So this is what the trial structure looks like. We show them a face, they respond, and then you see that they're provided with feedback: right, that was a happy face, or wrong. And in a very small, open, active trial of only 14 patients, we actually demonstrate that, indeed, the balance point shifted such that patients rated ambiguous faces as more happy following the trial. So we see here, this is post-treatment, one week and up to two weeks later. And there was also improvement in clinician-rated irritability; that is, the irritability ratings decrease at the end of treatment and up to one week later. Moreover, the parents rated their child as less irritable following the treatment up to two weeks later.

However, and there's a really big however here, as I said, this was an open, active trial. What's that mean? That means that all of the patients, all of the clinicians doing the ratings, and all the parents knew that the children were receiving this open active treatment. So it is possible that all this improvement we see could simply be due to expectancy effects by the child, by the clinician and by the parents.

So we're actually currently completing a RCT, a randomized controlled study now. Here, half the children get this active interpretation bias training whereby we're actively shifting that balance point to rate those ambiguous spaces as more positive, and half the children get a sham or a pretend interpretation bias training whereby we're simply reinforcing their initial balance point. And here we're now getting blinded clinical ratings, that is the clinicians doing the ratings don't know if the children are in that active group where their balance point is being moved or in the sham treatment, the placebo treatment whereby their initial balance point is simply being reinforced. And in fact, it's a very exciting time for us because we randomized our last child last week and will begin to look at this data, and we've randomized 40 patients, in the coming weeks, and I hope to update everyone on these findings soon.

So you could see how the interpretation bias training really targets that abhorrent threat processing that we see in youth, that bottom part of the model. But we also really need to address the abnormalities in reward processing and the top of the model, as well as the interaction of both aspects of the model which are synergistic. And we're doing this through cognitive behavioral therapy. So cognitive behavioral therapy, or CBT is a [talks?] therapy or psychotherapy that examines the relations between behavior, thoughts, and symptoms, and it draws very heavily upon behavioral principles. And we know from the literature that one of the effective cognitive behavioral treatment is exposure for anxiety.

So here, patients with anxiety are treated through gradually being exposed to their feared stimulus. So what we're doing now is applying those exposure principles to frustration. That is, during sessions, we're purposely and very carefully exposing irritable children to frustrating situations, and then helping them tolerate the physical and emotional discomfort they feel in the moment. So we came to this idea because we know that irritability shares many features with anxiety pathophysiologically, that is, in the brain, and clinically, which I'll talk more about in a moment.

So specifically, the hypothesis is that exposure to anger-inducing stimuli with anger-toleration will lead to muted or shorter responses to those same anger-inducing stimuli without those behavioral temper-outbursts so turning back to our model, we're testing whether exposure to threat and frustration with anger toleration will help to normalize the threat, reward, and threshold for angry and aggressive responses. Why did we choose exposure as an intervention?

First, as I mentioned, there's been profound efficacy of exposure in the treatment of anxiety. And irritability and anxiety share many features. Both [use?] with irritability and anxiety show [adament?] responses to threat. So whereas youth with irritability tend to approach or engage or have an aggressive response to the threat, youth with anxiety have an avoid, freeze, or flee response to that threat. Also, in both irritability and anxiety, specific cues trigger phasic high-arousal states. So in irritability, the phasic high-arousal state is anger. And in anxiety, that phasic high-arousal state is fear. And if you think about it, both anger and fear are elicited by a specific stimulus. And when that stimulus is encountered in both anger and fear, there tends to be an acute rise of the emotion, a peak, and then it tends to be of a specific duration. And we also focus on the deficits observed in instrumental learning in youth with irritability. And this draws on the very large literature prior work showing the efficacy of parent management training, which is another form of psychotherapy for clinical syndromes such as Disruptive Behavior Disorders like Oppositional Defiant Disorder.

So this is a 12 session manualized psychotherapy, which primarily works with the child, although there are numerous parent modules as well. So what do we do in our CBT? Well first, it's essential to assess safety to determine what outbursts look like and how to engage in exposures in a safe way. We also have to get child buy-in through motivational interviewing which really target that oppositionality we often see [inaudible]. And we acknowledge that anger can be useful. But together, we work as detectives in determining how the child's irritability may be causing them some difficulties in their life. And we engage in classic psychoeducation examining the relationships between thoughts, feelings, and behaviors, and we establish a common vocabulary that the kids and parents use to describe their feelings of anger and irritability. But that primary active ingredient is we conduct exposures.

So similar to the method used in anxiety. So how do we conduct anger-inducing exposures? We generate a hierarchy. But here it's an anger-inducing hierarchy, and then we work our way up to the hierarchy in [vivo?], that is, during the session. And we use this anger thermometer to concretely identify different levels of situations or events to include in our anger hierarchy. So just to kind of provide people with a  concrete details here. For example, as I discussed during an interview with the Wall Street Journal, one little boy I worked with got particularly angry when he was asked to complete his household chores. His household chore was sorting the clean laundry. When he was asked to sort the clean laundry, he would go into his room, knock over his bookshelf, throw his belongings around, and generally have a pretty moderate to severe temper outburst. So what did we do? Well, I asked his mom to bring in a bag of clean laundry for us to use in session. I poured it on the table. And at first, he just looked at the clean laundry pile, and I got an anger temperature rating. And then he would sort a sock or two, and I got a temperature rating. And each week, his mother would bring in a bag of clean laundry, the patient was able to sort more and more of the laundry each time with less anger, such that by the end of our work together, I'd pour out the clean laundry bag. He'd sort it. And we'd get on to the real business at hand. And in fact, his ability to sort the clean laundry did actually extend to his household chores in the home environment. And he was ultimately able to do this without temper outbursts.

Other exposures can include asking a child to stop playing a video game or start having the child do homework. Or if you really want to up the ante, have the child stop playing the video game and then switch to having to start doing some really boring homework. We sometimes rig things so that the child is losing a game, such as Uno or Checkers, and particularly if it's rigged or there's some type of rule violation which this unfairness can really often induce anger. And finally, we have parent sessions where we conduct a functional analysis of parenting behaviors.

And again, here we're drawing very heavily on learning theory, teaching parents to really reward and focus on positive behavior. Be very very consistent in their reward contingencies. And actively ignore non-dangerous irritable behavior. So here are some very preliminary open active data from ten patients we've seen over the past year or so, but given the very small sample size, we take these findings with a very large grain of salt. And then that being said, we do see improvements in clinician ratings of overall disruptive mood disregulation disorder in gray in the upper lefthand box. And this is done using the clinical global impressions improvement rating. We see improvements by mid-treatment. And then really a moderate amount of improvement by the end of the treatment. And we see large effect sizes for irritability related impairment in green. And we see this pretty profoundly over the course of the 12-week session. We also see large effect sizes in temper outbursts graphed here in red. And interestingly, you see here in blue that we actually had the least amount of improvement, although some, in that kind of generally cranky mood. And this is something we're really thinking about deeply and trying to target more.

So based on this pilot work, we feel this research is worth pursuing to test the efficacy of exposure for irritability. And we're actually now just beginning the next phase of this research using a multiple baseline study with randomized start times. And we'll have weekly clinical ratings by clinicians who are now blind to when the child is starting that active treatment or B here in the graph. We will include EMA or Ecological Momentary Assessment which is a real-time digitally based event sampling method whereby we can assess symptoms and clinically phenotype in vivo by providing smartphones with prompts to both the parent and child. And we will be exploring neural mechanisms to really understand that model I showed earlier by using threat and frustration functional magnetic residence imaging tasks pre and post-treatment.

So hopefully, I've addressed these four main questions. What is irritability? Why I think it's really important to study irritability? And how we're actually studying irritability in the intramural program of NIMH? And based on that work, what are some of the new treatments growing out of our research? And in conclusion, hopefully, I've convinced you that irritability is a very important clinical phenotype and clinical presentation for us to study due to the prevalence of it and the profound public health implications. I see our work as an iterative process whereby we're developing and testing mechanisms, behavioral and brain-based mechanisms, and targets of the treatment, and then probing those targets. We see those two core deficits in irritability as adherent responses to frustration and threat, as I showed in the heart of the model. And based on those two main targets, we've developed two mechanism-based treatments. And I've demonstrated preliminary efficacy for two studies, our computer-based interpretation bias training targeting threat and our exposure-based cognitive behavioral therapy also targeting threat as well as frustration and instrumental learning through the parent component. And we're probing neuro targets or brain-based areas in the context of both of these studies.

So finally, it's essential that I acknowledge the very large team who has supported this work, especially Dr. Ellen Leibenluft, Dr. Danny Pine, Dr. Argyris Stringaris and Dr. Katarina Kircanski. As well as numerous other collaborators here at the NIMH as well as in the extramural community. And of course, most importantly, the patients and their families that dedicate their time to our research. Finally, we're continuing to actively recruit, particularly for the cognitive behavioral study, and if you're interested, I've highlighted the number here. 301-496-8381. And we also have an email address. irritablekids@mail.nih.gov.