Irritability in Youth - PowerPoint Presentation

Irritability in Youth Katharina Kircanski, PhDEmotion and Development Branch, National Institute of Mental Health October 20, 2018

No conflicts to disclose Research is funded by the NIMH Intramural Research Program

Outline What is irritability? Why is it important to study irritability? How are we studying irritability at NIMH? What are some new treatments for irritability?

Case Example Nine-year old, “JP” has had chronic grouchiness and temper problems his whole life. At age 4, JP was asked to leave preschool because of his behavior and was diagnosed with ADHD. He continued to have chronic grouchiness and temper outbursts when frustrated. These occurred daily at home and weekly at school. Most outburst were verbal, but some were physical. Most recently, he was diagnosed with Disruptive Mood Dysregulation Disorder.

What is Irritability? Increased proneness to anger relative to peers Brotman et al., 2017 Duration Threshold Frequency Angry more often Angry for longer More easily annoyed

Components of Irritability Behavioral and emotional componentsOutbursts: Motor activity; verbal/physical aggressionMood: Persistently angry, grumpy, cranky Brotman et al., 2017

What is a Temper Outburst? Behavioral (physical) and emotional response to frustration or blocked goal attainment Snapping Mild arguing Name calling Yelling, screaming Verbal threats Physical displays (kicking, break belongings) Clenching fists, raising arm to hit Using object in way to harm Pushing, kicking Shoving, slapping

What is Blocked Goal Attainment? Time to get off the iPad Turn off the TV Start doing homework We are having meatloaf for dinner Clean up your room Can’t come over for a playdate No soccer game this weekend Time to turn in homework You lose the game Can’t go to the toy store right now

Emotional Manifestations Not specific outbursts, but general level of grouchiness or grumpiness Grumpy Grouchy “Wake up feeling off” Crabby Irritable mood “Walking on eggshells” Approach in “just the right way” Cranky

Why is Studying Irritability Important? Public health impactIrritability one of the most common reasons youth referred for psychiatric evaluation and care (Peterson et al., 1996)Irritability  adult impairment (Copeland et al., 2014) Academic problems PovertySuicidalityDSM-5 created Disruptive Mood Dysregulation Disorder (DMDD) in 2013

Disruptive Mood Dysregulation Disorder (DMDD) Severe, recurrent temper outbursts Verbal rages or Physical aggression toward people/property Out of proportion; inconsistent with developmental level>3 times per weekPersistently irritable or angry mood most days Present 2 of 3 (home, school, peers), impairmentOnset prior to age 10, cannot be made before age 6No hypo/mania

Irritability present in multiple diagnoses Bipolar Disorder Major Depressive Disorder ADHD Generalized Anxiety Disorder Separation Anxiety Disorder Social Anxiety Disorder Panic Disorder PTSD Oppositional Defiant Disorder Conduct Disorder Why did DSM Create a New Diagnosis? Autism Spectrum Disorders

Children who were characterized by chronic irritability did not have a category in the DSM In fact, there was controversy!Chronically irritable children were being diagnosed as having bipolar disorder Why did DSM Create a New Diagnosis?

Controversy: Irritability & Bipolar Disorder Bipolar disorder (BD) characterized by episodes of mania and depression Change in mood from baseline Hypothesis: BD in youth not episodicInstead, characterized by severe, chronic irritability and ADHD Implications for treatment, prognosis, prevalenceADHD and irritability in youth more common than BD

BD in parents of youth with episodic BD, but not in parents of chronically irritable youth (Brotman et al., 2007)Similarities and differences in behavioral and brain correlates (Leibenluft, 2011) If BD presents in children as chronic irritability… …then chronically irritable children should be at increased risk to develop BD as they age Controversy: Irritability & Bipolar Disorder

Longitudinal Outcomes of Irritability depressionanxiety ADHD BDCDODDsubstance Specificity : depression anxiety ODD Not bipolar disorder Vidal-Ribas et al., 2016 9 cohorts; N=7,594 Irritability prevalent ~ 3% Brotman et al., 2006

Why Does it Matter? Treatment!!!If DMDD = BD, then antipsychotic medication, lithium Stimulants and SRI’s relatively contraindicated If DMDD = ADHD + anxiety and/or depression, then stimulants and SRI NIMH-funded trials of stimulant + SRI vs. placebo Psychological treatment implications

Clinical Recap Irritability is characterized by behavioral and emotional componentsSevere irritability is not pediatric bipolar disorder Longitudinally, irritability is associated with risk for anxiety, MDD, and impairment Irritability DSM-5 Disruptive Mood Dysregulation Disorder (DMDD)

Outline What is irritability? Why is it important to study irritability? How are we studying irritability at NIMH? What are some new treatments for irritability?

Translational Model of Irritability (Brotman et al., Am J Psychiatry 2017) Environment Deficits in instrumental learning (Content) Deficits in instrumental learning (Process) Decreased threshold Aberrant reward processing IFG/PFC, striatum, ACC, amygdala Aberrant threat processing PFC, amygdala-hypothalamus-PAG Response ↑ Motor activity ↑ Aggression ↑ Anger ↑ Frustration Public health importance of irritability  model to understand brain and behavioral components, and guide new treatment development “Translational”  based on evolutionarily conserved processes and animal research

Associations between irritability and abnormalities in reward and threat processing Environment Deficits in instrumental learning (Content) Deficits in instrumental learning (Process) Decreased threshold Aberrant reward processing IFG/PFC, striatum, ACC, amygdala Aberrant threat processing PFC, amygdala-hypothalamus-PAG Response ↑ Motor activity ↑ Aggression ↑ Anger ↑ Frustration Translational Model of Irritability (Brotman et al., Am J Psychiatry 2017)

Neutral Faces Brotman et al., 2010 How afraid are you of this face? Irritable youth report higher levels of fear of neutral faces. Neutral face  threatening 1 = not at all…5 = very

# “angry” responsesOrdered Morphs (Happy to Angry) H Ambiguous Faces Penton- Voak et al., 2013 Stoddard et al., 2016 Maoz et al., 2017 … … H H H A A A A H Forced choice happy vs. angry Shown in randomized order Balance point Morph at which there is a shift in interpretation

p <0.001 Proportion angry judgments Morph —HV (N=26)— DMDD (N=63 ) Stoddard et al., 2016 Irritable Youth Rate Ambiguous Faces as More Angry Treatment???

Outline What is irritability? Why is it important to study irritability? How are we studying irritability at NIMH? What are some new treatments for irritability?

Assess … … Assess Time Baseline balance point Feedback threshold Train x 6 Angry judgments Happy judgments Training Blocks Penton- Voak et al., 2013 Stoddard et al., 2016 X Interpretation Bias Training (IBT)

+ ? Right! That face was happy. Fixation (1500-2500 ms ) Face (150 ms ) Mask (250 ms ) Response Window (Until Response) Feedback (1500 ms) Stoddard et al., 2016 Interpretation Bias Training (IBT)

Stoddard et al., 2016 Balance point changed after active training  rate ambiguous faces as more happy Clinical Global Improvement following training Parent-reported irritability decreased following training However…. Interpretation Bias Training Results completing RCT now

Cognitive Behavioral Therapy (CBT) Exposure to frustration with toleration of discomfort Irritability shares features with anxietyAberrant responses to threat (approach, avoid)Specific cues trigger phasic, high-arousal states Both anger and fear elicited by stimulus  acute rise, peak, durationHypothesis : Exposure to anger-inducing stimuli with toleration, leads to muted and/or shorter responses to stimuli without temper outbursts

Safety Motivational interviewingTargets oppositionality (What do you like/not like?)Acknowledge that anger can be useful, but problems Psychoeducation Establish common vocabulary anger/irritabilityExposureHierarchy, in-session exposure Household chores, stop playing video, homework, losing game Role play (peers, parents, siblings) Parent sessions Functional analysis of parenting behaviors Learning theory: reward positive; consistency; active ignore CBT Manual Components 10 Really, really angry 5 Medium angry 0 Not at all angry

CGI-S Overall DMDD Clinician ARI: Irritable MoodClinician ARI: Temper Outbursts Clinician ARI: Impairment Pre- to Post-Treatment Effect Size d = 0.88 (large) Pre- to Post-Treatment Effect Size d = 1.22 (large) Pre- to Post-Treatment Effect Size d = 0.97 (large ) Pre- to Post-Treatment Effect Size d = 0.64 (medium) Pre-Tx Mid-Tx Post-Tx Pre-Tx Mid-Tx Post-Tx Pre-Tx Mid-Tx Post-Tx Pre-Tx Mid-Tx Post-Tx CBT Preliminary Outcomes N=10 Open active Kircanski …. Brotman 2018

Multiple Baseline Design Within-subjects, randomized start timesEcological Momentary Assessment (EMA)Real-time, digitally based event sampling: assess symptoms, clinically phenotype in vivo (parents & children) In session-adherence as proxy for “dose”Threat & frustration fMRI Subject 1 A A A A B B B B B B B B B B B B 2 A A B B B B B B B B B B B B 3 A A A A A A B B B B B B B B B B B B 4 A A B B B B B B B B B B B B N Weekly c linical assessments Weeks

Outline What is irritability? Why is it important to study irritability? How are we studying irritability at NIMH? What are some new treatments for irritability?

Trajectory: Chronic irritability not a form of bipolar disorderIrritability  anxiety and depressionTranslation: Using neuroscience to study irritability Reward and threat processing Treatment: ImplicationsInterpretation Bias TrainingCognitive Behavioral Therapy Take-Away Messages

Thanks to: Melissa Brotman, PhDEllen Leibenluft, MDDanny Pine, MD Argyris Stringaris, MD Intramural collaborators Extramural collaboratorsWan-Ling Tseng, PhD Ned Kalin, MD (Wisconsin, Bench to Bedside 2018 award)Simone Haller, PhD Wendy Silverman, PhD (Yale) Ken Towbin , MD Eli Lebowitz, PhD (Yale) Ashley Smith, PhD Jack Hettema, PhD (VCU) Rany Abend, PhD Roxann Roberson-Nay, PhD (VCU) Julia Linke, PhD Rob Althoff, MD (University of Vermont, ENIGMA) Elise Cardinale, PhD Michelle Craske, PhD (UCLA) Pablo Vidal-Ribas, PhD Laurie Wakschlag, PhD (Northwestern) Gang Chen, PhD William Copeland, PhD (Duke) Rick Reynolds, MS Joel Stoddard, MD (UC Denver, Consultant NIMH K23) Robert Cox, PhD Jillian Wiggins, PhD (SDSU, Consultant NIH UL1TR001442) Rebecca Hommer, MD Andrea Gold, PhD (Brown) Bruno Averbeck, PhD Abigail Marsh, PhD (Georgetown, Consultant University Grant) SMDN Clinicians and IRTAs Giovanni Salum, MD ( Federal University of Rio Grande do Sul, Brazil) Patients and their families

37 Email: irritablekids@mail.nih.gov