1. Bipolar Disorder in Children: Diagnosis and Pathophysiology Ellen Leibenluft, M.D. Mood and Anxiety Program, NIMH Department of Psychiatry Georgetown University Hospital

2. Diagnosing bipolar disorder in children: The controversy Are symptoms chronic or episodic? Adults with bipolar disorder have EPISODES of mania and depression Do manic children have elation, or only irritability? Should children with extreme irritability and ADHD- like symptoms, but no distinct manic episodes, be diagnosed as bipolar?

3. Manic Episode: DSM-IV Criteria: What’s unique to bipolar disorder? A.Distinct period of abnormally and persistently elevated, expansive, or irritable mood, lasting >1 week (4 days for hypomania) B. During the mood disturbance, at least 3 (if elevated mood) or 4 (if irritable mood): 1.Inflated self-esteem or grandiosity 2.Decreased need for sleep 3.More talkative than usual 4.Flight of ideas 5.Distractibility 6.Increased goal-directed activity or psychomotor agitation 7.Excessive involvement in pleasurable activities

4. Manic Episode: DSM-IV Criteria: Overlap with ADHD A.Distinct period of abnormally and persistently elevated, expansive, or irritable mood, lasting >1 week (4 days for hypomania) B. During the mood disturbance, at least 3 (if elevated mood) or 4 (if irritable mood): 1.Inflated self-esteem or grandiosity 2.Decreased need for sleep ??? 3.More talkative than usual 4.Flight of ideas 5.Distractibility 6.Increased goal-directed activity or psychomotor agitation 7.Excessive involvement in pleasurable activities

5. “ Developmental modifications” in diagnostic criteria for BD Assumption: Youth with BD have cycles too rapid to be detected using adult techniques WASH-U: change definitions of episodes and cycles cycles > 4 hours (Geller et al, 2004) Assumption: Instead of elation, youth with mania have very extreme irritability rather than elation MGH: episode criterion waived if irritability is very severe (Mick et al, 2005)

6. Irritability in Childhood-Onset Disorders  Major depressive episode  Manic episode  Oppositional defiant disorder  Anxiety disorders  PDD-spectrum disorders  ADHD  Conduct disorder

7. Differences across research groups in phenomenology of pediatric BPD From Axelson et al, 2006 WASH-U: mean # daily cycles= 3.5 + 2.0

8. Advantages of using adult conventions It works, as long as you use developmentally appropriate symptom thresholds Can compare adults and youth Can (cautiously) generalize from the extensive adult literature Data indicate that severely, chronically irritable children with ADHD differ from those with BD in outcome, family history, brain mechanisms

9. Defining the controversial group: “Severe mood dysregulation” Chronic: persistent sx’s; no distinct episodes of mania Irritable: reactivity to negative emotional stimuli > 3x/wk baseline anger/ sadness ADHD-like symptoms: > 3 “B” mania criteria e.g., agitation, distractibility Very impairing Leibenluft et al, 2003

10. Parents of BPD youth more likely to have BD than are parents of SMD children % BPD OR 15.82, CI 1.91-130.98, p=.01; Chi-square p<.01 Brotman et al, submitted

11. SMD children in the Great Smoky Mountain Study Longitudinal epidemiologic data set (Costello et al) N= 1,420, 4 waves, ages 9-18 Questions What is the prevalence of SMD? Answer: 3.2% What is the diagnostic outcome of children with SMD at the last wave (mean age 18.3 + 2.1 y)?

12. What diagnoses are SMD at high risk for at mean age=18.3 + 2.1 y? ** Odds Ratio Brotman et al, 2006

13. Chronic irritability in youth predicts later MDD Chronic irritability at age 14 predicts MDD at age 22 OR= 2.29 (1.22-4.31) (Leibenluft et al, 2006) Oppositional defiant disorder at age 7 predicts MDD at age 18: OR=1.06 (1.01-1.10) (Burke et al, 2005) Familial association between MDD and disruptive behavior disorders (Weissman et al, 2005)

14. Diagnosis: Summary The diagnosis of bipolar disorder should be reserved for children who have clear episodes of mania. Elation during mania is common in children with bipolar disorder. Children with severe irritability and “hyperarousal” are at high risk for major depression, not necessarily bipolar disorder.

15. Pathophysiology: Children with bipolar disorder have difficulty processing facial emotion

16. Why study processing of facial emotions in pediatric BD? Patients with mood disorders have problems processing face emotion Brain circuitry of face processing well-studied Children learn to regulate emotion in part by learning to label emotion

17. Clinical characteristicsBD (N=84) Age 12.8 + 3.0 Gender (% male) 54.8 Age of onset 10.1 + 3.3 % ADHD57.1 % Anxiety d/o77.4 % BP I79.8 % with hx hospitalization 56.3 Mean # medications 3.1 + 1.4 Children’s Global Assessment Scale 47.6 + 13.7

18. MORPH 39 0% INTENSITY MORPH 32 21% INTENSITY MORPH 24 41% INTENSITY MORPH 1 100% INTENSITY MORPH 16 62% INTENSITY MORPH 8 82% INTENSITY Gradations of Emotional Expression RJR Blair

19. Fewer Morphs Needed More Morphs Needed * * * * BD require more intense emotional info to identify facial emotion *p<.01 Rich et al, submitted

21. Face emotion labeling errors: BPDs make more than all other groups…except SMDs Number of errors Guyer et al, in press F(4,251)=4.81, p<.001F(4,267)=7.41, p<.001 a a a Post hoc analyses: a p<=.001 b p<=.01 c p<=.05 b c Note: SMD also more errors than MDD+ANX on child faces (p=.017) a

22. DANVA errors in children at-risk for BD F(2, 132)=9.52, p<.001F (2,147)=12.64, p<.001 Number of errors ** Brotman et al, unpub *= p<.01

23.  Left Amygdala Volume in Pediatric BPD Dickstein et al, 2005 -24, 5, -15 t=3.64 p=.01

24. Faces fMRI task design How hostile is this person? How afraid are you? How wide is the nose?

25. Ratings of Neutral Faces: BP ratings abnormal only in emotional contexts p=.008p=.61p=.004 Rich et al., 2006 Rating

26. Hostile neutral vs. nose width neutral BD (N=22) vs. controls (N=21) tpxyz 3.56.001-226-16 2.77.004-2620-18 K E = 239 P<.005 whole brain uncorrected Rich et al, 2006

27. Pathophysiology: Summary Children with bipolar disorder have deficits identifying facial emotion. This deficit is also present in children at risk for bipolar disorder. Compared to controls, children with bipolar disorder see neutral faces as more negative, and have more amygdala activation when viewing such faces.