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What is New in Bipolar Spectrum Disorders in Youth?

The Child and Adolescent Bipolar Spectrum Services (CABS) Studies

Boris Birmaher, M.D.Distinguish Professor of Psychiatry

Endowed Chair in Early Onset Bipolar DisorderUniversity of Pittsburgh School of Medicine

Western Psychiatric Hospitalwww.pediatricbipolar.pitt.edu

•All Families for their participation

• Investigators and Staff. Many people have worked countless hours over the last 20 years to gather, maintain, analyze and interpret the data

• Staff of the Child and Adolescent Bipolar Services (CABS)

• Funding our studies

•National Institute of Mental Health

• The Alicia Koplowitz Foundation (Spain)

• The Fine Foundation (Pittsburgh)

Thank You

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• National Institute of Mental Health (NIMH) grants

• Royalties• Up to Date

• Random House: “New Hope for Children and Teens with Bipolar Disorder” 2004 • Book Chapters

Disclosures

Pediatric Bipolar Disorder

• All adult studies done by independent investigators have shown that up to 60-70% of adults with bipolar disorder began to have mood symptoms before age 25

• As evidenced by our and other pediatric studies, bipolar usually onsets during adolescence

• However, bipolar disorder can also appear during childhood. Unfortunately, still some professionals do not recognize it

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J is an ? year boy with

• Ongoing typical symptoms of ADHD and behavior problems that responded to stimulants plus therapy

• Periodically, without any obvious stressors, the above symptoms worsen, and it “seems” that the stimulant is “no longer working”

• During these periods he is:• very energetic• many ideas at the same time • sometimes he has grandiose ideas (e.g., believes he can fly from a third-floor balcony to the

pool and needs to be restrained)• Sleeps 2-3 hours per night for 3 days without being tired the next day or needing to take a nap• If interrupted, he can become very aggressive to the point that once he needed hospitalization

• The above symptoms cluster together and manifest on average every 2-3 months and last 3-4 days, but his sleep and demeanor can be disruptive for up to 2 weeks

• Parents observed these symptoms since early childhood. A parent had similar symptoms

J is an 8 year boy with

• Ongoing typical symptoms of ADHD and behavior problems that responded to stimulants plus therapy

• Periodically, without any obvious stressors, the above symptoms worsen, and it “seems” that the stimulant is “no longer working”

• During these periods he is:• very energetic • many ideas at the same time • sometimes he has grandiose ideas (e.g., believes he can fly from a third-floor balcony to the

pool and needs to be restrained)• Sleeps 2-3 hours per night for 3 days without being tired the next day or needing to take a nap• If interrupted, he can become very aggressive to the point that once he needed hospitalization

• The above symptoms cluster together and manifest on average every 2-3 months and last 3-4 days, but his sleep and demeanor can be disruptive for up to 2 weeks

• Parents observed these symptoms since early childhood. A parent had similar symptoms

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Pediatric Bipolar Disorder (cont’)

• The prevalence for pediatric bipolar disorder I and II is estimated to be 1-2%

• It’s associated with poor psychosocial functioning and increased risk to develop behavior and legal problems, substance abuse and suicidality.

• Therefore, the need:• For those who have not developed bipolar, who is a risk to develop

this disorder• For youth who already have bipolar disorder, who is at risk for

recurrences• Develop better psychotherapies and pharmacology treatments to

prevent or delay onset and prevent recurrences• Find biological markers to inform diagnosis and treatment

To address these issues our group performed, among others, two large longitudinal studies

The Course and Outcome of Bipolar Youth (COBY)

The Pittsburgh Bipolar Offspring Study (BIOS)

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The Course and Outcome of Bipolar Youth (COBY)

Course and Outcome of Bipolar Youth (COBY)

▪ Multicenter Study (Universities of Brown, UCLA, and UPMC)

▪ Children and adolescents with Bipolar Disorder - I, II and NOS

▪ Interviews with youth and parents about: mood, behavior, life events, treatment, cognition, school and family functioning, medical problems (including inflammatory markers), and neurocircuits

▪ On average, follow-up every year

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COBY intake data (n = 438)

▪ Mean age: 12.7 years old

▪ 53% Male

▪ 82% Caucasian

▪ Most Middle Class

▪ Living with both biological parents: 42%

▪ 58% Bipolar Disorder type I, 35% Bipolar-NOS and 7% Bipolar II

▪ Age of onset: 9.3 3.9 years old (SD:3.9)

▪ Duration: 3.3 2.5 years

Birmaher et al., AJP, 2009; Axelson et al., Arch Gen Psych, 2006

COBY Defined BD-NOS

• Most youth were given diagnosis of BD-NOS because of the DSM duration requirement for mania/hypomania

• Like youths with bipolar disorder type I and II they showed:

• Poor psychosocial functioning

• Presence of comorbid disorders • Risk for substance abuse

• Risk for suicidal ideation and attempts

• High family history of mania

• Similar genetic structure

About 50% converted into BD-I/II, specially if they have family history of BD

Axelson et al., 2006, 211; Birmaher et al., 2006, 2009, 2014

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Suicidal Attempts

• About 50% history of lifetime suicidal attempts

• Females > Males

• No differences among bipolar subtypes

• Predictors 8-weeks before a suicide attempt (important for prevention):• Greater number of weeks spent with threshold depression

• Substance use disorder

• Mixed mood symptoms

Goldstein Tina et al., Bipolar Disord. 2005; Jama Psychiatry. 2012

Substance Abuse

• About 48% lifetime history of substance abuse• Most during the follow-up (important for prevention)• Many ≥2 substances• Cannabis followed by alcohol • No differences among bipolar subtypes

Goldstein Ben et al., Bipolar Disord, 2008 Journal Am Academy of Child Adoles Psy, 2013

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Other findings

• Increased service utilization (e.g., hospitalizations)• Family conflicts• Poor psychosocial functioning• Academic difficulties• Exposure to negative events (e.g., physical and/or

sexual abuse)• Increased weight• Psychosis• Polypharmacy- lithium seems to be specific to

prevent suicidality

4-year follow-up of 413 youth with Bipolar Spectrum Disorders:

% Follow-Up Time Euthymic (stable mood) or Symptomatic for the Group

As a Whole

Bipolar-IBipolar-IIBipolar-NOS

~40%Subclinical

~20%Syndromal

~40% Euthymic

Most:MixedRapid cyclingDepression

4 years follow-up

Birmaher et al., Am J Psychiatry, 2009

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Percentage of time spent with mood symptoms between youth with

Bipolar -I/II (Birmaher et al., 2009) vs. adults with Bipolar-I/II (Judd et

al., 2002)

Are there sub-groups with different trajectories? Different Longitudinal Mood Courses based on the percentage of time asymptomatic during 9 years

of follow-up (n=367)

“predominantly euthymic “24%

“predominantly ill”22%

Birmaher et al., AJP, 2015

“moderately euthymic”34.6%

“ill with improving course”19%

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Predictors of Recurrence/Worse Course (important for the identification and prevention of recurrences)

Mood Recurrence/

Worse Course

Mood onset<12 years old

Subthreshold Mood Symptoms

Low Socioeconomical Status

More previous recurrences

Family history of mania and substance abuseComorbid Disorders

Severe Mood Symptoms/Suicidality/Psychosis

Negative Events (e.g. abuse)

A patient with BD walks into your clinic. He/she is doing well. Can you predict the risk of a mood recurrence for this specific patient?

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We know the risk for COBY sample as a whole- What about an Individual’s Risk ?

For example, Risk Factors for Myocardial Infarction:

age, sex, severity, blood pressure, cholesterol, excercise, diet, family

history etc.

Individualized Risk Estimate

Inform Treatment

0.65

0.70

0.75

0.80

0.85

0.90

0.95

0 6 12 18 24 30 36 42 48 54 60

Are

a U

nd

er C

urv

e

Months of Prediction

Area Under the Curve by Recurrence Polarity and Length of Prediction Interval

Any Polarity Major Depression Mania/Hypomania

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What Now

• New study Predicting Recurrences in Bipolar Illness (PROMPT-BD)

• Better treatments to improve functioning (interpersonal, family, academic etc), well-being, and prevent recurrences

• Better treatments for comorbid conditions and medical problems

• Biological markers (Neuroimaging, genetics etc)

The Pittsburgh Bipolar Offspring Study (BIOS)

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The Pittsburgh Bipolar Offspring Study (BIOS)

• Case-control high-risk study

• Recruit parents who have BP-I or II and child/adolescent offspring (ages 6-18)

• Demographically match community control parents with child/adolescent offspring

• Assess participants longitudinally (every 2 years) using diagnostic/dimensional assessments

Parents

• Total Sample: 377

• Bipolar: 236 (70% BD-I; 30 % BD-II)

• Controls: 141 (with and without non-BD psychopathology)

Parents with BD had more disorders than controls

The same was true for biological co-parents

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School-age Offspring - Demographics

• Total Sample: 639• Offspring of parents with BD: 388

• Offspring of controls: 251

• ~ 12 years

• ~ 50% females

• ~ 80% Caucasian

• ~ 65% Tanner Stage: I-III

• ~ 50% living with both biological parents

Offspring –Lifetime (intake + follow-up) DSM Disorders

0

10

20

30

40

50

60

70

80

High-Risk Offspring %

Comparison Offspring %

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Cumulative rate of bipolar spectrum disorders (Panel A) and BD-I/II (Panel B) by Age

For bipolar spectrum diagnoses (panel A): high-risk offspring > comparison offspring; log-rank χ2 = 40.2; p=2.3×10−10For first manic or hypomanic episode (panel B): high-risk offspring > comparison offspring; log-rank χ2=19.2; p=1.2×10−5

23%

3.2%

12.7%

1.5%

Axelson et al., AJP, 2015

Onset of depression and non-mood disorders relative to onset of Bipolar Spectrum Disorders

34.7%

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Which factors can help to identify who is at risk to develop bipolar disorder

• Significant mood lability (irritability), ongoing symptoms of depression/anxiety and subsyndromal manic symptoms

• Parental bipolar disorder, especially if the onset of the parental bipolar symptoms was early in life (e.g., before 21 years old)

•Up to 50% of children with all these factors are at risk develop bipolar disorder

Hafeman et al., 2016

Comparison of Several Polygenic Risk Scores (PRS) between

Parents with and without Bipolar Disorder (BD)

Birmaher et al., under review

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Comparison of Several Polygenic Risk Scores between Offspringof Parents with BD vs. Offspring of Parents without BD

Predicting Risk to Develop Bipolar Disorder

Parental Bipolar Polygenic Risk Score

Parental Diagnosis of Bipolar Disorder

Offspring Bipolar Polygenic Risk Score

Offspring Risk to Develop Bipolar

Disorder

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What Now?

• Treatments to delay the onset of bipolar disorder or in the best of cases prevent it (Tina Goldstein, Danella Hafeman, Ben Goldstein)

• Genetic studies

• Neuroimaging studies (Mary Phillips, Amelia Versace, Michelle Bertocci)

• Medical consequences and how to prevent them (Ben Goldstein)

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