Is Pediatric Bipolar Disorder a Valid Disorder?...Risperidone in the Treatment of Pediatric Bipolar...

Is Pediatric Bipolar Disorder a Valid Disorder?

Joseph Biederman, MD

Professor of Psychiatry

Massachusetts General Hospital

Disclosures 2009-2011

n Research Support:

q Eliminda, J&J, Shire, NIH, Philanthropy

n Honoraria:

q Fundacion Areces, Medice, Spanish Child Psychiatry Association, Fundacion Cabral, Monterey Mexico, MGH Academy

Pediatric BPD: History of a Controversy

n 1960: Childhood mania exists but is rare (Anthony and Scott)

n 1970-1980: Childhood mania may be more common than we thought (Weller et al., Carlson et al.)

q It may be under-diagnosed due to developmentally variable symptom expression

n 1990-2000: Childhood mania is a serious source of morbidity in child psychiatric clinics (Biederman et al., Geller et al.)

n 2000-2010: Childhood mania is over-diagnosed and over-treated (or is it?)

Pediatric Mania

May 26, 2008 issue

Parens et al. N Engl J Med. 2010 May 20;362(20):1853-5

Moreno et al. Arch Gen Psychiatry 2007;64(9):1032-39

National Trends in Visits with a Diagnosis of Bipolar Disorder as a Percentage of Total Office-Based Visits by Youth (aged 0-19 years) and adults (aged >20

years)

National Trends in Visits with a Diagnosis of Bipolar Disorder as a Percentage of Total Office-Based Visits

0

5

10

15

20

25

1994 1995 1996 1997 1998 1999 2000 2001 2002 2003

Moreno et al., Arch Gen Psych, 2007)

Most bipolar adults in STEP-BD reported onset in childhood or adolescence

n 65% of adults with onset < 18

n Almost a third with onset < 13

> 18 years:35%

13 to 18 years37%

< 13 years28%

Perlis, Miyahara, Marangell, Wisniewski, Ostacher, DelBello, Bowden, Sachs, Nierenberg, Biol Psych 2004;55:875-881

Bipolar adults with childhood and adolescent onset had more lifetime suicide attempts and violence

0

10

20

30

40

50

60

70

80

Suicide Attempts Violence Psychotic Features

Child

Adolescent

Adult

Perlis, Miyahara, Marangell, Wisniewski, Ostacher, DelBello, Bowden, Sachs, Nierenberg, Biol Psych 2004;55:875-881

N=983

Population Studies of Bipolar Disorder and Severe Mood Dysregulation in Youth

*from Van Meter et al., JCP, in press

Without New

Diagnosis:

1,271,819

With New

Diagnosis: 2,907

(0.23%)

Number of Patients with a New Diagnosis of Bipolar Disorder by Age Group

Olfson et al. Psychiatric Services 2009; 60(8):1098-1106.

Diagnosed <7: 4.5%

Diagnosed 7-12: 24.8%

Diagnosed 13-17: 70.7%

0.04% 0.16% 0.44%

5.90%

0.00%

2.00%

4.00%

6.00%

8.00%

10.00%

12.00%

14.00%

16.00%

18.00%

20.00%

Age <7 Age 7-12 Age 13-17 Age 18-29

Rates of New Bipolar Disorder Diagnoses by Age Group

Kessler et al. Archives of General

Psychiatry2005;62:593-602

Olfson et al. Psychiatric Services 2009; 60(8):1098-1106

Robins & Guze Criteria for Validity of Psychiatric Diagnosis

n Clinical presentation

n Family history

n Treatment response

n Course and outcome

n Laboratory studies

Clinical Presentation

Euphoric

Euphoria and Irritability in BPD Probands

Irritable

Are All Forms of Irritability the Same?

Heterogeneity of Irritability

Months

Incr

easi

ng

Sev

erit

y

1 3 5 7 9 11 13 15 17 19 21 23 25 27 29 31 33 35 37 39 41 43 45 47

ADHD ODD MDD MANIA

Heterogeneity of Irritability in Children

Mick et al, 2007

0

10

20

30

40

50

60

70

80

90

100

ADHD (N=274) Non-Mood ADHD (N=144)

Pe

rce

nt

Geller et al (2002) JCAP

ODD Irritability Mad/Cranky Super Angry/Grouchy/ Cranky

Stratified Prevalence of Irritability in ADHD Subjects With and Without Mood Disorder

Mick et al. Biological Psychiatry, 2005; 58:576-582.

Juvenile Mania

n The type of irritability observed in manic children is very severe, persistent, and often violent.

n The outbursts often include threatening or attacking behavior towards others, including family members, other children, adults, and teachers.

Biederman et al. J Am Acad Child Adolesc Psychiatry. 1996; 35(8): 997-1008.

Heterogeneity of Irritability

n Labile mood/hot temper: ODD

n Severe irritability: MDD

n Explosive/violent irritability: BPD

Mick et al. Biological Psychiatry. 2005; 58:576-582.

Differential Diagnosis with ADHD

n Overlapping symptoms include:

a) Distractibility

b) Physical hyperactivity

c) Talkativeness

p< 0.05 vs. ADHD females

p< 0.05 vs.ADHD males

Biederman et al. Psychological Medicine. 2006; 36: 167-179.Biederman et al. Biological Psychiatry. 2006; 60: 1098-1105.

Bipolar Disorder in Girls and Boys With and Without ADHD

0

10

20

30

40

Control Females Control Males ADHD Females ADHD Males

%

ADHD Baseline Control Follow-up

ADHD Follow-up

Kessler et at. Am J Psychiatry. 2006; 163:4

Patterns of Comorbidity in ADHD Adults

Bipolar disorder

0 1 2 3 4 5 6 7 8

Social phobia

PTSD

Panic disorder

Obsessive-compulsive disorder

Major depressive disorder

intermittent explosive disorder

Dysthymia

Drug dependence

Any substance use disorder

Any mood disorder

Any anxiety disorder

Alcohol dependence

Odds Ratio

Clinical Presentation:

Two Cohorts

1) Assessed in the arly 1990’s

2) Assessed 1995-2002

2002 MGH Study of Pediatric BPD

ADHD

N=450

BPD

N=112 N=17

Biederman et al. J of Affective Disorders. 2004; S82:45-58.

Diagnostic Overlap of BPD and ADHD [Second Cohort]


BPD Illness Age of Onset

p=NS


4.4

BPD 1st Cohort

4.8

BPD 2nd Cohort

0

2

4

6

8

10

12

Years(mean)



0

20

40

60

80

100

Chronic Episodic

Rapid Cycling

Episodic

Multiple Prolonged Episodes

Single Prolonged Episode

Single Brief Episode%


p=NS

BPD Illness Duration


0

2

4

6

8

10

12

3

BPD 1st Cohort

3.5

BPD 2nd Cohort

Years(mean)


P=NS

P=NS

P=NS P=NS

P=NS

Comorbid Disorders by Bipolar Cohort


0

20

40

60

80

100

MajorDepression

Psychosis ADHD OppositionalDefiant Disorder

ConductDisorder

%

Bipolar 1st Cohort Bipolar 2nd Cohort


P=NS

P<0.001

Treatment History: Hospitalization


0

5

10

15

20

25

30

21

Bipolar 1st Cohort

23

Bipolar 2nd Cohort

2

ADHD 2nd Cohort

%

Clinical Presentation

n Frequently irritable

n Frequently non-episodic

n Frequently chronic

n Frequently mixed

n Highly comorbid with ADHD, ODD, CD, and anxiety


Is Pediatric BPD Familial?

0

2

4

6

8

10

12

14

16

18

20M

orb

id R

isk i

n R

ela

tives

BP-I ADHD Control

Familial Risk of BP-I Disorder in First Degree Relatives

Proband n= 157 162 136

Relative n= 508 511 411

P <0.01 vs. ADHD and Controls

*

*

Wozniak et al. In Press


Does Pediatric BPD have

a unique course?

Types of Remission

n Syndromatic Remission

q Loss of full diagnostic status

n Symptomatic Remission

q Loss of subthreshold diagnostic status

n Functional Remission

q Loss of subthreshold diagnostic status with functional recovery

Keck et al. American Journal of Psychiatry. 1998:155:5.

27%

73%

6%5%9%

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

Remission Persistence

%

Figure 1. Persistence of DSM-IV BP-I in youth at 4-year Follow-up

Full DSM-IV BP-I

SubthresholdDepression

Treated

Wozniak, Biederman et al. 2010 in press

Persistence of DSM-IV BP-I in youth at 4-year Follow-up

Full BP-I disorder73.1%

Subthreshold BP-I disorder6.4%

Full or subthreshold MDD5.1%

Treated9.0%

Euthymic6.4%

Wozniak, Biederman et al. 2010 in press


Does Pediatric BPD have

unique laboratory findings?

MRI Findings

Thalamus

Hippocampus

Cerebral Cortex

Amygdala

Frazier et al. 2003.

Bipolar MRI Results

Ino: myo-InositolCho: cholineCr: creatineGlx: glutamate and glutamineNAA: N-acetyl aspartate

Moore et al. Am J Psychiatry. 2006; 163: 316-318.

Proton Spectrum (b) acquired from the anterior cingulate cortex (a) of a child with bipolar disorder


Does Pediatric BPD have a unique pharmacological response?

Pharmacologic Dissection Strategy:ADHD and BPD Naturalistic Study

Biederman et al. J Clin Psychiatry. 1998; 59: 628-637.

6

5

4

3

2

1

0Mood

StabilizersStimulants

Red

uct

ion

of M

ania

(Rat

e R

atio

)P = 0.03

P = 0.4

Frazier et al. J Child Adolesc Psychopharmacol 2001 11(3): 239-250

Olanzapine in the Treatment of Pediatric Bipolar Mania: Change in YMRS Total Score from Baseline to Endpoint

Tohen et al. AJP 2007; 164:1547–1556

OPEN LABEL 8-WEEK STUDY (n=23) DOUBLE BLIND 3-WEEK STUDY (n=161)

***p<0.001

-17.65 points, p<0.001

-19 points

-14 points

Mean dose: 9.6 4.3mg/day Mean dose: 8.9mg/day

CGI-S of Mania: 40% improvement, p<0.001

Mean Weight Gain: 5.0 2.3kg, p<0.001

Biederman et al. CNS Spectr 2007; 12(9)

-15 points, p<0.001

-14 points, p<0.0001

Nyilas et al (2008) APA Meeting

Aripiprazole in the Treatment of Pediatric Bipolar Mania: Change in YMRS Total Score from Baseline to Endpoint

OPEN LABEL 8-WEEK STUDY (n=19) DOUBLE BLIND 4-WEEK STUDY (n=296)Mean dose: 9.4 4.2mg/day

Mean Weight Gain: 1.8 1.7kg, p=.2

Mean Weight Gain: 0.55kg, p>0.5

Risperidone in the Treatment of Pediatric Bipolar Mania: Change in YMRS Total Score from Baseline to Endpoint

-18.5 points, p<0.001

-14.4 points, p<0.0001

Biederman et al. J Child Adolescent Psychopharmacology 2006; 15(2): 311-317 Pandina et al. (2007) AACAP Meeting

OPEN LABEL 8-WEEK STUDY (n=30) DOUBLE-BLIND 3-WEEK STUDY (n=137)

Mean Weight Gain: 1.9 1.7kg

Mean dose: 1.25 1.5 mg/day

Mean Weight Gain: 2.1 2.0kg; p<0.001

-15

-10

-5

00 1 2 3 4 5 6 7 8

Week, Post-Baseline

YM

RS

To

tal S

co

re

Me

an C

hang

e fro

m B

ase

line

(L

OC

F)

F(8,17)= 1.2, p=0.4

Wozniak et al. CNS Spectrums 2008 submitted

Divalproex ER in the Treatment of Pediatric Bipolar Mania: Change in YMRS Total Score from Baseline to Endpoint

-7 points, p=0.4

-8.8 points, p = .604

Wagner et al., JAACAP 48:5, May 2009

OPEN LABEL 8-WEEK STUDY DOUBLE BLIND 4-WEEK STUDY (n=229)

Mean Weight Gain: 1.0kg; p>0.05

Is Pediatric BPD Without the Distinct Episode Qualifier a Valid Clinical Entity?

n Fully satisfies Robins & Guze criteria for a valid clinical entity

n Severe and highly dysfunctional clinical presentation highly consistent with adult bipolar disorder

n Positive family history of BPD

n Selective treatment response to antimanic agents

n Compromised course and outcome

Is Mood Instability Characterized by Severe Irritability and Frequent Absence of Discrete Episodes in Children, BPD?

n Chronic and severe irritability and absence of discrete episodes may represent developmentally specific associated features of pediatric onset BPD.

n “Atypical” form is the most common presentation of BPD in children.

First scientific article to present a coherent conceptual perspective on Pediatric Bipolar Disorder as a developmental subtype of Bipolar Disorder

Is Pediatric Bipolar Disorder a Valid Disorder?...Risperidone in the Treatment of Pediatric Bipolar...

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