Embed Size (px)
Citation preview
www.mghcme.org
Pediatric Bipolar Disorder and ASD
Janet Wozniak, MD
Associate Professor of Psychiatry
Massachusetts General Hospital
www.mghcme.org
Disclosures
My spouse/partner and I have the following relevant financial relationship with a commercial interest to disclose:
Royalties (Spouse): Cambridge University Press, UptoDate Consultation Fees (Spouse): Advance Medical, FlexPharma, Merck
Research Support (Spouse): UCB Pharma, NeuroMetrix
www.mghcme.org
Scope of the Problem: Population Studies of Bipolar Disorder and Related Disorders in Youth
2.9
1
0.7
1.5
1.3
6.3
0
2.8
0.7
1.2
1.8
2.4
0
2.5
0 1 2 3 4 5 6 7
Merikangas 2010 USA
Lewinsohn 1995 USA
Kashani 1987 USA
Andrade 2006 USA
Gould 1998 USA
Kessler 2009 USA
Costello 1996 USA
Verhulst 1997 Dutch
Holtzmann 2010 German
Stringaris 2010 UK
Kim-Cohen 2003 New Zealand
Canals 1997 Spain
Lynch 2006 Ireland
Benjet 2009 Mexico
Percent with Disorder
Not USA:
1.9%*
USA: 1.7%*
*from Van Meter et al., JCP, in press
www.mghcme.org
SCOPE OF THE PROBLEM Merikangas, et al, National Comorbidity Survey Replication-Adolescent Supplement
J Am Acad Child Adolesc Psychiatry. 2010 Oct;49(10):980-9
www.mghcme.org
Most bipolar adults in STEP-BD reported onset in childhood or adolescence
• 65% of adults with onset < 18
• Almost a third with onset < 13
> 18 years:
35%
13 to 18 years
37%
< 13 years
28%
Perlis, Miyahara, Marangell, Wisniewski, Ostacher, DelBello, Bowden, Sachs, Nierenberg, Biol Psych
2004;55:875-881
www.mghcme.org
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
www.mghcme.org
Clinical Presentation
www.mghcme.org
DSM Mania Diagnosis
• Period of abnormally and persistently elevated, expansive or irritable mood and increased energy or activity (DSM5 addition) lasting 1 week or requiring hospitalization
• 3 of the following criteria (4 if irritable) – Grandiosity Distractibility
– Less sleep Goal-directed activity
– Pressured speech Excessive pleasurable activity
– Flight of ideas
www.mghcme.org
Regular Kid! typical
Manic level SEVERE
IRRITABILITY:
swearing, disrespectful, threatening, wild, out of control with Explosions that are frequent, for 30-60+ minutes, destructive, aggressive
Euphoric:
Giddy, goofy, silly, high, “on drugs,” laughing fits
Irritability of Depression:
angry, grouchy, cranky, whiney, complaining, difficult to please, short-tempered
Melancholy:
sad, no pleasure, down on self, suicidal, self-destructive
The most severe types of emotional dysregulation comes
when mania and depression co-occur in
the mixed states of bipolar disorder
www.mghcme.org
Euphoric
Euphoria and Irritability in BPD Probands
Irritable
www.mghcme.org
A DAY IN THE LIFE OF A BIPOLAR CHILD IS A ROLLER COASTER OF MOODS
• 10 year old Laura was cranky and miserable all day refusing her mother’s suggestions for fun activities.
• After a phone from a friend she was talking a ‘mile a minute’ with excitement over a school party, exaggerating her popularity.
• She demanded her mother buy her a new cell phone to use to text about the party and, when her mother refused, required a physical hold for over 60 minutes after she exploded in anger.
• Before bed, she sobbed and sobbed and told her mother ‘How can you love me? I cause you so much trouble. You should just kill me.’
www.mghcme.org
Are All Forms of Irritability the Same?
Heterogeneity of Irritability
www.mghcme.org
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
www.mghcme.org
Juvenile Mania
• The type of irritability observed in manic children is very severe, persistent, and often violent.
• 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.
www.mghcme.org
Heterogeneity of Irritability
• Labile mood/hot temper: ODD
• Severe irritability: MDD
• Explosive/violent irritability: BPD
Mick et al. Biological Psychiatry. 2005; 58:576-582.
www.mghcme.org J Am Acad Child Adolesc Psychiatry. 1995 Jul;34(7):867-76
16% of a children 6-12 years of age in a clinic sample (N=262) met full criteria for mania
www.mghcme.org
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]
www.mghcme.org
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)
www.mghcme.org
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)
www.mghcme.org
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
Major Depression
Psychosis ADHD Oppositional Defiant Disorder
Conduct Disorder
%
Bipolar 1st Cohort Bipolar 2nd Cohort
www.mghcme.org
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
%
www.mghcme.org
ACCOMPANYING EDITORIAL BY AUTISM EXPERT Peter Tanguay, MD
“I suggest that the authors have mistaken the manifestations of difficult
temperament in young children with autism for mania……Those of us who deal
with children with PDD know that 10% to 20% of them also have a difficult
temperament.”
-
Our earliest work on the combined condition of
mania and autism was met with skepticism by the
autism research community
J Am Acad Child Adolesc Psychiatry. 1997 Nov;36(11):1552-9
www.mghcme.org
ORI GI NA L PA PER
The Heavy Burden of Psychiatr ic Comorbidity in Youthwith Autism Spectrum Disorders: A Large ComparativeStudy of a Psychiatr ically Referred Population
Gagan Joshi • Car ter Petty • Janet Wozniak •
Aude Henin • Ronna Fr ied • Mar ibel Galdo •
Meghan Kotarski • Sarah Walls • Joseph Bieder man
Published online: 23 March 2010
Ó Springer Science+Business Media, LLC 2010
Abstract The objective of the study was to systemati-
cally examine patterns of psychiatric comorbidity in
referred youth with autism spectrum disorders (ASD)
including autistic disorder and pervasive developmental
disorder not otherwise specified. Consecutively referred
children and adolescents to a pediatric psychopharmacol-
ogy program were assessed with structured diagnostic
interview and measures of psychosocial functioning.
Comparisons were made between those youth satisfying
diagnostic criteria for ASD and age and sex matched youth
without ASD referred to the same clinical program. 9.3%
(217/2323) of the referred youth (age range: 3–17 years)
met DSM-III-R criteria for ASD. ASD youth suffered from
significantly higher number of comorbid disorders than
comparisons (6.4 ± 2.7 vs. 5.2 ± 2.9; p\ 0.001). Ninety-
five percent of the youth with ASD had three or more
comorbid psychiatric disorders and 74% had five or more
comorbid disorders. ASD youth were also more function-
ally impaired and required extra-assistance in school and
therapeutic interventions at higher rates than age and sex
matched non-ASD referred youth. Youth with ASD have
high levels of psychiatric comorbidity and dysfunction
comparable to the referred population of youth without
ASD. These findings emphasize the heavy burden of psy-
chiatric comorbidi ty afflicting youth with ASD and may be
important targets for intervention.
Keywor ds Autism spectrum disorders
Psychiatric comorbidity Children and adolescents
Introduction
Autism spectrum disorders (ASD) refers to a group of
developmental disorders distinguished by variable presen-
tation of difficul ties with socialization, communication,
and behavior that are estimated to affect at least 7 in 1,000
children and adolescents in the general population (CDC
2006; Fombonne 2003). Much higher rates of ASD ranging
from 2 to 14% have been reported in youth referred for
psychiatric care, thereby comprising a substantial subgroup
of patients referred for psychiatric treatment (Sverd et al.
1995; Sverd 2003; Wozniak et al. 1997a, b).
While the reason for psychiatric referrals of children
with ASD are heterogeneous, they are frequently driven by
emotional and behavioral symptoms including irritabil ity
and aggression (RUPP 2002), hyperactivi ty (RUPP 2005),
anxiety (Gadow et al. 2004, 2005), and depression (Vick-
erstaff et al. 2007; Sterling et al. 2008). However, whether
these co-occurring emotional and behavioral symptoms
represent associated features in children with pervasive
developmental disorders (PDD; American Psychiatric
Association 2000), or bona fide comorbid psychiatric dis-
orders remains unclear (Frazier et al. 2001).
Comorbid psychiatric symptoms have been reported in a
number of questionnaires studies in both children (Herring
G. Joshi C. Petty J. Wozniak A. Henin R. Fried
M. Galdo M. Kotarski S. Walls J. Biederman
Pediatric Psychopharmacology Research Department,
Massachusetts General Hospital, Boston, MA, USA
G. Joshi C. Petty J. Wozniak A. Henin R. Fried
J. Biederman
Harvard Medical School, Boston, MA, USA
G. Joshi (& )
55 Fruit Street, YAW 6A, Boston, MA 02114, USA
e-mail: [email protected];
123
J Autism Dev Disord (2010) 40:1361–1370
DOI 10.1007/s10803-010-0996-9
Author's personal copy
www.mghcme.org
0 20 40 60 80 100
Cigarette Smoking
Substance Use Disorders
Psychosis
Bipolar I Disorder
Major Depressive Disorder
Multiple (≥2) Anxiety Disorders
Conduct Disorder
Oppositional Defiant Disorder
Attention-deficit/Hyperactivity…
Percentage
ASD NON-ASD
***
Statistical Significance: *p≤0.05, **p≤0.01, ***p≤0.001
***
Diagnoses in Psychiatrically Referred Youth with and without ASD
N=2323
J Autism Dev Disord. 2010 Nov;40(11):1361-70
www.mghcme.org
0
20
40
60
80
100
Extra help Special class Repeated grade
Controls ADHD BPD-I BPD-I+ASD
%
Statistical Significance: *p≤0.05, **p≤0.01, ***p≤0.001 A = vs. Control; B = vs. ADHD; C = vs. BPD
A***
School Functioning
A***
A***
A***
B**
A***
AB***C**
A***
AB*
0
20
40
60
80
100
Controls ADHD BPD-I BPD-I+ASD
Hospitalization
AB***
A
B
*
*
*
0
%
Autism Complicates the Course of Bipolar Disorder
J Clin Psychiatry 2013;74(6):578–586
www.mghcme.org
0
20
40
60
80
100
ElatedMood
IrritableMood
Grandiosity DecreasedSleep
PressuredSpeech
Flight ofIdeas /Racing
Thoughts
Distractibility PoorJudgment
Increase inActivity
BPD-I+ASD BPD-I
Symptoms of Mania in BPD Youth with and without Autism
%
*
***p≤0.001 Statistical Significance: *p≤0.05, **p≤0.01, ***p≤0.001
J Clin Psychiatry 2013;74(6):578–586
www.mghcme.org
Summary of Clinical Presentation
• Frequently irritable
• Frequently non-episodic
• Frequently chronic
• Frequently mixed
• Highly comorbid with ADHD, ODD, CD, anxiety and ASD
www.mghcme.org
Is Pediatric BPD Familial?
www.mghcme.org
0
2
4
6
8
10
12
14
16
18
20
BP-I ADHD Control
Mo
rbid
Ris
k i
n R
ela
tives
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. Psychol Medicne 2011
www.mghcme.org
Bipolar Disorder in First-Degree Relatives A family history of bipolar disorder is present in
bipolar youth with and without autism
3.6 4.3
12.5 12.4
0
2
4
6
8
10
12
14
Controls(N=411)
ADHD(N=511)
BPD(N=336)
BPD+ASD(N=137)
Statistical Significance: *p≤0.05, **p≤0.01, ***p≤0.001 A = vs. Control; B = vs. ADHD
A**B***
%
AB***
J Clin Psychiatry 2013;74(6):578–586
www.mghcme.org
Does Pediatric BPD have a unique course?
www.mghcme.org
Persistence of DSM-IV BP-I in youth at 4-year Follow-up
Full BP-I disorder
73.1%
Subthreshold
BP-I disorder
6.4%
Full or
subthreshold MDD
5.1%
Treated
9.0%
Euthymic
6.4%
Wozniak, Biederman et al. 2010
www.mghcme.org
Does Pediatric BPD have a unique pharmacological response?
www.mghcme.org
Academic Debate
“The unfortunate reality is that current medications help too few people to get better and very few people to get well.”
- Thomas Insel
NIMH Director
NEJM 362;20. May 20, 2010.
www.mghcme.org
1989 to 2010: FDA-Approved Medications for PBD
• 1989-2007 Lithium • 2007 Risperidone • 2008 Aripiprazole • 2009 Olanzapine • 2009 Quetiapine
www.mghcme.org
Many FDA Approved Treatments for Children
and Adolescents with Emotional Dysregulation
– Lithium: manic or mixed states, patients aged 13-17 years – Risperidone: manic or mixed states, age 10-17 years – Aripiprazole: manic or mixed states, age 10-17 years – Olanzapine: manic or mixed states, age 13-17 years – Quetiapine: monotherapy or adjunct to lithium or divalproex sodium,
manic states, age 10-17 years – Saphris manic or mixed episodes assoc with BPD I, age 10-17
– Fluoxetine: depression and OCD age 8+ – Escitalopram: depression age 12+ – Sertraline,fluvoxamine, anfranil: pediatric OCD
– Aripiprazole: irritability associated with autistic disorder ages 6-17 – Risperidone: irritability associated with autism ages 5-16
www.mghcme.org
Liu et al. J Am Acad Child Adolesc Psychiatry 2011; 50(8): 749-762.
www.mghcme.org
Studies of Pediatric Mania Psychopharmacology 1989 - 2010
• 40 Published Studies – 28 Open
Label
– 12 RCT
• 2704 Subjects participated across studies
2
13 13
1
3
8
0
2
4
6
8
10
12
14
1989-1999 2000-2005 2005-2010
Open Label
RCT
Year
Num
ber
of
Stu
die
s
www.mghcme.org
Mean Change in YMRS from Baseline by Medication Class
-10.99 -11.03
-16.8
-5.6
-18
-16
-14
-12
-10
-8
-6
-4
-2
0
Traditional MoodStabilizers
OtherAnticonvulsants
AtypicalAntipsychotics
NaturopathicTreatments
YM
RS
Sco
re
www.mghcme.org
BPD-ASD
84% (N = 128)
BPD+ASD
16% (N = 23)
CNS Neurosci Ther. 2012 Jan;18(1):28-33
Bipolar Youth with Autism Included in Clinical Trials of SGAs for Bipolar Youth
N=151
www.mghcme.org
28
40
34
43
35
42 38
49
0
10
20
30
40
50
60
YMRS CDRS ADHD-RS BPRS
BPD-PDD BPD+PDD
p < 0.001 p= 0.04 NS NS
Rating Scales in BPD Youth with and without Autism N=151
CNS Neurosci Ther. 2012 Jan;18(1):28-33
www.mghcme.org
69
47
65
44
0
10
20
30
40
50
60
70
80
YMRS ( ≥30%) YMRS ( ≥50%)
BPD-PDD BPD+PDD
NS
NS
Anti-Manic Response of Bipolar Youth to SGA Monotherapy: No difference with and without ASD
N=151
CNS Neurosci Ther. 2012 Jan;18(1):28-33
www.mghcme.org
N-ACETYLCYSTEINE
www.mghcme.org
Funding/support: This study was supported by a generous philanthropic donation from Kent and Elizabeth Dauten (Chicago, Illinois).
November 2015
www.mghcme.org
0
10
20
30
40
50
60
70
80
90
CGI MDD Improvement≤2
30% HAM-DImprovement
50% HAM-DImprovement
30% CDRSImprovement
50% CDRSImprovement
Perc
ent
of
Sub
ject
s
Inositol (n=7) Omega-3 FA (n=7) Omega-3 FA + Inositol (n=10)
0
OR=2.50
OR=2.50 OR=3.75
OR=3.00
OR=2.37
HAM-D SMD (Omega-3 FA vs. Inositol)=0.51 HAM-D SMD (Omega-3 FA + Inositol vs. Inositol)=0.56
CDRS SMD (Omega-3 FA + Inositol vs. Inositol)=0.59
0
OR=2.37
OR=1.00
OR=1.88
OR=1.60
OR=1.88
OR=2.00
OR=1.00
OR=1.67
OR=1.67
HIGH EPA OMEGA-3 FATTY ACIDS AND INSOSITOL IN PEDIATRIC BPD STUDY: ANIDEPRESSANT RESPONSE
Wozniak et al, JCP in press
www.mghcme.org
0
10
20
30
40
50
60
70
80
90
CGI ADHD Improvement≤2 CGI Anxiety Improvement≤2 CGI ODD Improvement≤2 30% BPRS Improvement
Perc
ent
of
Sub
ject
s
Inositol (n=7) Omega-3 FA (n=7) Omega-3 FA + Inositol (n=10)
0
OR=2.37
OR=3.11
OR=2.50
OR=5.83
OR=6.00
OR=2.40
OR=3.46
BPRS SMD (Omega-3 FA vs. Inositol)=0.77 BPRS SMD (Omega-3 FA + Inositol vs. Inositol)=0.60 CGI Anxiety SMD (Omega-3 FA + Inositol vs. Inositol)=0.55 CGI ODD SMD (Omega-3 FA + Inositol vs. Omega-3 FA)=0.45
OR=6.82
OR=8.08
0
OR=1.25
OR=1.88
OR=0.67
HIGH EPA OMEGA-3 FATTY ACIDS AND INSOSITOL IN PEDIATRIC BPD STUDY: OTHER RESPONSES
Wozniak et al, JCP in press
www.mghcme.org
PBD Mania Trials: Summary
• Significant increase in clinical trials of anti-manic agents over the past 10 years
• Atypical antipsychotic agents outperform traditional mood stabilizers and other anticonvulsants
www.mghcme.org
SUMMARY: Pediatric BP Disorder
• Severe and highly dysfunctional clinical presentation highly consistent with adult bipolar disorder
• Positive family history of BPD
• Selective treatment response to antimanic agents
• Compromised course and outcome
www.mghcme.org
SUMMARY: BP and ASD
• A clinically significant subgroup of individuals with ASD suffer from BP disorder
• Symptom of mania and familiality of BP disorder are similar in BP youth with and without ASD
• No differences in anti-manic response or tolerability to SGAs in BP diosrder youth with or without ASD
