Webinar: Severe Irritability in Youth

Webinar: Severe Irritability in Youth


>>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’ 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. [email protected]

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