Irritability in Youth Katharina Kircanski Ph D Emotion

Irritability in Youth Katharina Kircanski, Ph. D Emotion 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 Frequency Angry more often Duration Threshold Angry for longer More easily annoyed Brotman et al. , 2017

Components of Irritability • Behavioral and emotional components – Outbursts: Motor activity; verbal/physical aggression – Mood: Persistently angry, grumpy, cranky Brotman et al. , 2017

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

What is Blocked Goal Attainment? Turn off the TV Time to get off the i. Pad Start doing homework Can’t come over for a playdate Clean up your room We are having meatloaf for dinner Time to turn in homework No soccer game this weekend 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 Grouchy Grumpy “Wake up feeling off” “Walking on eggshells” Irritable mood Crabby Cranky Approach in “just the right way”

Why is Studying Irritability Important? • Public health impact • Irritability 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 – Poverty – Suicidality • DSM-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 week • Persistently irritable or angry mood most days • Present 2 of 3 (home, school, peers), impairment • Onset prior to age 10, cannot be made before age 6 • No hypo/mania

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

Why did DSM Create a New Diagnosis? • 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

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

Controversy: Irritability & Bipolar Disorder • 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

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

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 components • Severe 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) Aberrant reward processing IFG/PFC, striatum, ACC, amygdala Decreased threshold Response ↑ Anger ↑ Frustration ↑ Motor activity ↑ Aggression Aberrant threat processing PFC, amygdalahypothalamus-PAG • 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

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

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

Ambiguous Faces H H H A … A A A … 3 # “angry” responses Forced choice happy vs. angry 2 Shown in randomized order Balance point Morph at which there is a shift in interpretation 1 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 Ordered Morphs (Happy to Angry) Penton-Voak et al. , 2013 Stoddard et al. , 2016 Maoz et al. , 2017

Proportion angry judgments Irritable Youth Rate Ambiguous Faces as More Angry p<0. 001 —HV (N=26) —DMDD (N=63) Morph Treatment? ? ? Stoddard et al. , 2016

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?

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

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

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

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

CBT Manual Components • Safety • Motivational interviewing 10 Really, really angry – Targets oppositionality (What do you like/not like? ) – Acknowledge that anger can be useful, but problems • Psychoeducation – Establish common vocabulary anger/irritability • Exposure 5 Medium angry – Hierarchy, 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 0 Not at all angry

CBT Preliminary Outcomes N=10 Open active CGI-S Overall DMDD 5 Clinician ARI: Impairment 8 7 4 6 5 3 4 2 1 0 3 Pre- to Post-Treatment Effect Size d = 0. 88 (large) Pre-Treatment Mid-Treatment Post-Treatment Pre-Tx Mid-Tx 2 1 0 Post-Tx 12 12 10 10 8 0 Mid-Tx Post-Tx 6 6 2 Mid-Treatment Post-Treatment Clinician ARI: Irritable Mood 14 4 Pre-Treatment Pre-Tx Clinician ARI: Temper Outbursts 8 Pre- to Post-Treatment Effect Size d = 1. 22 (large) 4 Pre- to Post-Treatment Effect Size d = 0. 97 (large) Pre-Treatment Pre-Tx Mid-Treatment Post-Treatment Mid-Tx Post-Tx 2 0 Pre- to Post-Treatment Effect Size d = 0. 64 (medium) Pre-Treatment Mid-Treatment Post-Treatment Pre-Tx Mid-Tx Post-Tx Kircanski…. Brotman 2018

Multiple Baseline Design Subject Weeks 1 A A B B B 2 A A B B B 3 A A A B B B 4 A A B B B N Weekly clinical assessments • Within-subjects, randomized start times • Ecological 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 f. MRI

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?

Take-Away Messages • Trajectory: Chronic irritability not a form of bipolar disorder – Irritability anxiety and depression • Translation: Using neuroscience to study irritability – Reward and threat processing • Treatment: Implications – Interpretation Bias Training – Cognitive Behavioral Therapy

Thanks to: Melissa Brotman, Ph. D Ellen Leibenluft, MD Danny Pine, MD Argyris Stringaris, MD Intramural collaborators Wan-Ling Tseng, Ph. D Simone Haller, Ph. D Ken Towbin, MD Ashley Smith, Ph. D Rany Abend, Ph. D Julia Linke, Ph. D Elise Cardinale, Ph. D Pablo Vidal-Ribas, Ph. D Gang Chen, Ph. D Rick Reynolds, MS Robert Cox, Ph. D Rebecca Hommer, MD Bruno Averbeck, Ph. D SMDN Clinicians and IRTAs Extramural collaborators Ned Kalin, MD (Wisconsin, Bench to Bedside 2018 award) Wendy Silverman, Ph. D (Yale) Eli Lebowitz, Ph. D (Yale) Jack Hettema, Ph. D (VCU) Roxann Roberson-Nay, Ph. D (VCU) Rob Althoff, MD (University of Vermont, ENIGMA) Michelle Craske, Ph. D (UCLA) Laurie Wakschlag, Ph. D (Northwestern) William Copeland, Ph. D (Duke) Joel Stoddard, MD (UC Denver, Consultant NIMH K 23) Jillian Wiggins, Ph. D (SDSU, Consultant NIH UL 1 TR 001442) Andrea Gold, Ph. D (Brown) Abigail Marsh, Ph. D (Georgetown, Consultant University Grant) Giovanni Salum, MD (Federal University of Rio Grande do Sul, Brazil) Patients and their families

Email: irritablekids@mail. nih. gov 37