What is the Brain Teaching us About Child and Adolescent Psychiatric Disorders Update on Juvenile Bi

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What is the Brain Teaching us About Child and
Adolescent Psychiatric Disorders?Update on
Juvenile Bipolar Disorder ADHD
F. Xavier Castellanos, M.D. Brooke and Daniel
Neidich Professor of Child and Adolescent
Psychiatry Phyllis Green Randolph Cowen
Institute for Pediatric Neuroscience NYU Child
Study Center Nathan S. Kline Institute for
Psychiatric Research
30 March 2008
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Disclosures None

• NYU School of Medicine Nathan Kline Institute
  Employee
• U.S. National Institutes of Health Reviewer
  Consultant, Advisory Council (NIDA)
• University of Melbourne Miegunyah Visiting
  Fellow
• NARSAD, NIMH, NIDA, Niarchos Foundation Tourette
  Syndrome Association NYU CSC Research funding
• No income or research funding from commercial
  entities

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• Juvenile Bipolar Disorder
• Ellen Leibenluft et al.
• Bob Findling et al.
• Attention-Deficit/Hyperactivity Disorder
• Judy Rapoport et al.
• Neuroimaging Beyond the Introductory Phase
• NYU studies

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Juvenile Bipolar Disorder

• Ellen Leibenluft and colleagues
• NIMH cohort
• Great Smoky Mountain Study (Costello Angold)
• Children in the Community (Pat Cohen)
• Bob Findling and colleagues
• Case Western Longitudinal Assessment of Manic
  Symptoms sample

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Pediatric bipolar disorderthe controversy

• Do children with bipolar disorder have
  identifiable episodes, or is their presentation
  chronic (i.e., non-episodic)?
• Is severe irritability the defining feature of
  pediatric mania, or is euphoria?
• Should children with severe irritability and ADHD
  be diagnosed as bipolar?

Courtesy of Ellen Leibenluft, NIMH
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Severe Mood Dysregulation (SMD)

• No episodes of mania (DSM-IV episodes are 4
  days)
• Irritability defined
• baseline anger or sadness
• reactivity to negative emotional stimuli 3x
  / week
• Irritability impairing in 2 settings
• Comparably impaired as BD
• ADHD symptoms that overlap with B mania
  criteria

Courtesy of Ellen Leibenluft, NIMH
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GSMS - Last wave diagnoses SMD vs. non-SMD
youth (mean age18.3 2.1 y)

Odds Ratio
Brotman et al, 2006
Courtesy of Ellen Leibenluft, NIMH
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Children in the Community Study
(Cohen et al., 1993)

• Wave Age (y)
• 1 13.8 2.5
• 3 22.1 2.7
• Constructed continuous scales for chronic and
  episodic irritability
• Chronic irritability at time 1 predicts MDD at
  time 3 OR 2.29, CI 1.22-4.31
• Episodic irritability at time 1 predicts BPD at
  time 3 OR2.51 CI 1.01 - 6.26

Leibenluft et al, 2006
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Parents of BD youth more likely to have BD than
are parents of SMD children
BD
OR 18, CI 1.9-171, pBrotman et al, 2007
Courtesy of Ellen Leibenluft, NIMH
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Affective Posner BD and SMD more frustrated
than controls.
Courtesy of Ellen Leibenluft, NIMH
Rich et al, 2007
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But the brain mechanisms differexecutive
attention (P3 ERP amplitude at Pz)
Significant group x task interaction F(4,112)
2.67, p.04 Task 3 BPDs BPDs Courtesy of Ellen Leibenluft, NIMH
Rich et al, 2007
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Pediatric bipolar disorderprovisional answers

• Do children with bipolar disorder have
  identifiable episodes, or is their presentation
  chronic (i.e., non-episodic)?
• SMD is very common.about 3.2
• Comparable impairment different brain mechanisms
• Episodic irritability predicts mania, chronic
  irritability predicts depression.
• Is severe irritability the defining feature of
  pediatric mania, or is euphoria?
• Euphoria much more specific
• Should children with severe irritability and ADHD
  be diagnosed as bipolar?
• Likely premature pending

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Robert L. Findling, M.D.
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LAMS Specific Aims

• Prevalence of elevated symptoms of mania (ESM) in
  clinical settings
• Develop diagnostic criteria for a pediatric
  phenotype for bipolar disorder
• Identify characteristics of children who
  initially present with ESM who, over time,
  develop either BP1 or BP2
• Document factors associated with poor functional
  long-term outcome

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LAMS Subjects

• Children aged 6-12
• 600 children with elevated symptoms of mania
  (ESM)
• 60 children without elevated symptoms of mania
• Exclusion Criteria
• ESM due to general medical condition
• IQ

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Divalproex in the Prevention of Bipolar Disorder
in Subsyndromal High-Risk Children
Cyclothymia or BP NOS (5-17 years old)
DVPX N29
Randomize to monotherapy
YES
AND
Clinical Intervention
Up to 5 years
Placebo N27
Offspring of a parent with bipolar disorder
YES
D/C

• Significant symptoms of hypomania
• in past 2 months (YMRS13)

Findling et al., 2007
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Time to Discontinuation
p 0.93
Treatment Condition DVPX Placebo
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Number of Family Members with Emotional/Behavioral
Problems - Discontinuation
n 1 or 2
n 3
p0.03
p0.82
Treatment Condition DVPX, Placebo,

Parent queried if a known history of any
emotional/behavioral difficulties was present in
mother, father, sibling(s), and each grandparent
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Efficacy of Divalproex in the Prevention of
Bipolar Disorder in Subsyndromal High-Risk
Children

• Only having one parent at risk may not be an
  optimal study strategy for future high risk
  clinical trials

Findling et al., 2007
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Design of Open Stabilization Phase
Remission 4 weeks and CDRS-R 12.5 CGAS 51
BP-I or BP-II 5-17 years old
Randomize to monotherapy
DVPX Li Up to 20 weeks
283 screened 160 enrolled 139 dosed
Findling et al 2000 2003
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Spectrum of Effectiveness of Lithium Divalproex
in Juveniles vs. Adults
n0
Calabrese et al. 2005 Findling et al., 2003
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Phase 1 Findings

• Symptoms of depression and mania in youths with
  bipolar disorder may be substantially reduced
  during treatment with VPA Li
• Children are more responsive to treatment with
  VPA Li than adults
• Whereas depression is often the treatment
  resistant mood state in adults, in juvenile
  bipolarity, mania appears to be the treatment
  resistant affective state

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Design of Randomization Phase
DVPX N30
Remission Phase I
DVPX Li for 8 weeks
Clinical Intervention
Up to 76 weeks
Li N30
Findling et al. 2005
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DVPX vs Lithium in Juvenile Bipolar Disorder
Time to Discontinuation
Treatment Condition DVPX Lithium
p 0.60
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Post-hoc Analyses

• Younger age at onset were more likely to relapse
  to mood episode
• Higher YMRS scores at study baseline were more
  likely to discontinue the study early

• Factors NOT Associated with study discontinuation
  or mood relapse
• Age
• Co-morbid ADHD
• Rapid cycling
• Gender
• Length of illness
• Baseline CDRS-R scores
• Concurrent use of ADHD medications