Is Pediatric Bipolar Disorder a Valid Disorder?...Risperidone in the Treatment of Pediatric Bipolar...
Transcript of 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]
2002 MGH Study of Pediatric BPD
BPD Illness Age of Onset
p=NS
Biederman et al. J of Affective Disorders. 2004; S82:45-58.
4.4
BPD 1st Cohort
4.8
BPD 2nd Cohort
0
2
4
6
8
10
12
Years(mean)
Biederman et al. J of Affective Disorders. 2004; S82:45-58.
2002 MGH Study of Pediatric BPD
0
20
40
60
80
100
Chronic Episodic
Rapid Cycling
Episodic
Multiple Prolonged Episodes
Single Prolonged Episode
Single Brief Episode%
2002 MGH Study of Pediatric BPD
p=NS
BPD Illness Duration
Biederman et al. J of Affective Disorders. 2004; S82:45-58.
0
2
4
6
8
10
12
3
BPD 1st Cohort
3.5
BPD 2nd Cohort
Years(mean)
2002 MGH Study of Pediatric BPD
P=NS
P=NS
P=NS P=NS
P=NS
Comorbid Disorders by Bipolar Cohort
Biederman et al. J of Affective Disorders. 2004; S82:45-58.
0
20
40
60
80
100
MajorDepression
Psychosis ADHD OppositionalDefiant Disorder
ConductDisorder
%
Bipolar 1st Cohort Bipolar 2nd Cohort
2002 MGH Study of Pediatric BPD
P=NS
P<0.001
Treatment History: Hospitalization
Biederman et al. J of Affective Disorders. 2004; S82:45-58.
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
Robins & Guze Criteria for Validity of Psychiatric Diagnosis
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
Robins & Guze Criteria for Validity of Psychiatric Diagnosis
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
Robins & Guze Criteria for Validity of Psychiatric Diagnosis
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
Robins & Guze Criteria for Validity of Psychiatric Diagnosis
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