Pediatric Bipolar Disorder
Andel V. Nicasio, MSEd
University of Central Florida
7936 Child Psychopathology
October 9, 2013
Aims of this presentation
1.
2.
3.
4.
5.
Review the current DSM-5 definition and criteria for
bipolar disorder
Highlight major historical developments in the
scientific understanding of bipolar disorder
Illustrate the evolution of bipolar diagnosis on the
DSM
Review the literature on pediatric bipolar disorder
Present a new theoretical model for pediatric bipolar
disorder
Aim 1
•
Review the current DSM-5 definition and
criteria for bipolar disorder
What is Bipolar Disorder?

“Also known as manicdepressive illness, is a brain
disorder that causes unusual
shifts in mood, energy,
activity levels, and the
ability to carry out
day-to-day tasks.” NIH
DSM-5 Classification of BP
Bipolar I – (Depression & Mania)
 Bipolar II – (Depression and Hypomania)
 Cyclothymic Disorder
 Substance/Medication-Induced Bipolar and Related
Disorders
 Bipolar and Related Disorder Due to Another Medical
Condition
 Other Specified Bipolar and Related Disorder
 Unspecified Bipolar and Related Disorder

Bipolar Disorder in the DSM-5

DSM-5 highlights that
children and adolescents
who experience bipolarlike symptoms may not
meet criteria for BP-I, BP-2,
and cyclothymic disorders.
However, they may meet
criteria for Other Specified
Bipolar and Related
Disorder.
Bipolar I – DSM-5 Criteria



Manic Episode – may have been preceded by and many be
followed by hypomanic or MD episodes.
A. A distinct period of abnormally and persistently elevated,
expansive or irritable mood and persistently increased goaldirected activity or energy, lasting at least 1 week and
present most day, nearly every day.
B. During the period of mood disturbance and increased
energy or activity (three or more) of the following symptoms (4
if the mood is only irritable) are present…
Bipolar I – Manic Episode

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Inflated self-esteem or grandiosity
Decreased need for sleep
More talkative than usual or pressure to keep talking
Flight of ideas or subjective experience that thoughts are racing.
Distractibility
Increase in goal-directed activity or psychomotor agitation
Excessive involvement in activities that have a high potential for painful
consequences
C. The mood disturbance is sufficient severe to cause marked
impairment in social or occupational functioning or requires
hospitalization…or there are psychotic features.
D. The episode is attributable to the physiological effects of a
substance or another medical condition.
Hypomanic Episode


A. A distinct period of abnormality and persistently elevated,
expansive or irritable mood and persistently increased goaldirected activity energy or energy, lasting at least 1 week 4
consecutive days and present most day, nearly every day.
B. During the period of mood disturbance and increased energy
or activity (three or more) of the following symptoms (4 if the
mood is only irritable) are present…


Same list of symptoms as Mania
C. The episode is associated with an unequivocal change in
functioning that is uncharacteristic of the individual when not
symptomatic.
Cont…Hypomania



D. The disturbance in mood and
the change in functioning are
observable by others.
E. Episode is not severe enough to
cause marked impairment in social
or occupational functioning or
necessitate hospitalization…
F. Episode is not attributable to the
use of a substance…
Features a child who has been
playing since 1:30am - 10:30am.
Video taken around 10:30am
http://www.youtube.com/watch?v=Y4GYwymtbUU
VIDEO
Child with Bipolar Disorder
Manic Depressive Episode

A. Five (or more) of the following symptoms have been present the same
2-week period and represent a change in previous functioning; at least
one of the Sxs is depressed mood or loss of interest or pleasure.










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Depressed mood most of the day
Markedly lost of interest or pleasure in all, or almost all
Significant weight lost
Insomnia or hypersomnia
Psychomotor agitation or retardation nearly everyday
Fatigue or loss of energy
Feelings of worthlessness...guilt
Diminished ability to think or concentrate...
Recurrent thoughts of death, suicidal ideation...
B. Sxs cause significant distress or impairment…
C. The episode is not attributable to a substance or another medical
condition.
Bipolar II Disorder




Criteria have been met for at least one hypomanic episode
and at least one MD episode…
There has never been a manic episode.
The occurrence of hypomanic and MD is not better explained
by schizoaffective disorder…
The Sxs of depression or the alternation between periods (MD
and hypomania) causes clinically significant distress or
impairment…
Diagnostic Coding

Specifiers for BP-I and BP-II*:
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Current or Most Recent Episode*
Severity: Mild, Moderate, Severe*
With psychotic features
In partial remission, full remission*
With anxious distress*
With mixed features*
With rapid cycling*
With melancholic features
With atypical features
With mood-congruent psychotic features*
With mood-incongruent psychotic features*
With catatonia*
With peripartum onset*
With seasonal pattern*
Other Specified Bipolar and Related Disorder


This Dx is used when Sxs of Bipolar Disorder Spectrum are
present, but do not meet criteria for any one in particular.
Clinicians can specify the reasons why Sxs do not meet criteria
for other BPs, by using the other specified designation:
Short-duration hypomanic episodes (2-3 days) and MD
episodes
 Hypomanic episodes with insufficient Sxs and MD episodes
 Hypomanic episode without prior major depressive episode
 Short-duration cyclothymia (less than 24 months)

DSM-5 Model
What is the prognosis of child
diagnosed with bipolar disorder?
http://www.youtube.com/watch?v=WYxO8IjpF9k
VIDEO
Dr. Gabrielle Carlson (Feb. 2013)
Aim 2 & 3
•
•
Highlight major historical developments in the
scientific understanding of bipolar disorder
Illustrate the evolution of bipolar diagnosis on
the DSM
History - Hippocrates (460–337 BC)




Probably the first to systematically
describe melancholia and mania.
Formulated the first classification of
mental disorders: melancholia, mania,
and paranoia.
Suggested a connection between
mania and melancholia using humoral
theories.
‘‘Black bile’’ could generate a variety
of phenomena, depending on the
temperature.
Marneros , A. & Angst, J. (2000)
History – Relationship between Manic and
Melancholic States

Aretaeus of Cappadocia (2nd Century AD) - considered the ‘‘father
of bipolar disorder.’’ First to clearly described mania and
melancholia as being two components of one disease.

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
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‘‘It appears to me that melancholy is the commencement and a part of
mania.’’
Jean-Pierre Falret (1854) - “folie circulaire” - formally described the
sequential change from mania to melancholia and vice versa and
the symptom-free interval in between as a separate disease.
Jules Baillarger (1857) - ‘‘folie _a double forme’’ - mania and
melancholia changed into one another, but the interval between was
felt to have no meaning.
Falret and Baillarger (1894) - credited for discovering the bipolar
disorder.
Marneros, A. & Angst, J. (2000)
History – Manic-depressive Illness

Emil Kraepelin (1921)

Dichotomized the ‘‘endogeneous’’
psychoses into ‘‘dementia praecox’’ and
manic-depressive insanity.

Conducted systematic observations of over
900 patients suffering from "manicdepressive insanity“.

First to raise the possibility that children
could develop mania.

Children – prevalence rate higher among
15-20 y/o and only 0.4% in children < 10
y/o.
Kraepelin E. (1921). “Manic-depressive insanity and paranoia”
History – Unipolar vs. Bipolar



Karl Leonhard (1957) – classified Unipolar
Disorder (major depressive disorder) and
Bipolar Disorder.
Research by Karl Leonhard (German),
Jules Angst (Swiss), and Carlo Perris
(Scandinavian) supported:
 The nosology and family hx
differentiation between unipolar and
bipolar.
There is no unanimity even now about the
validity of these separations.
Manic Depression in US



Psychiatry was heavily influenced by
Psychoanalytic theories and the theories
of Adolf Meyer
Meyer (first half of 1900s) emphasized
the interaction between an individual’s
biologic and genetic characteristics and
the social environment.
This notion is included in the DSM-1
(1952), which includes a diagnosis of
‘‘manic-depressive reaction.’’
Kanner L. (1935).
DSM-I (1952)
DEPRESSION
 Psychotic Disorders
 Involutional psychotic reaction
 Affective reactions
 Manic depressive reactions



Psychotic depressive reaction
Psychoneurotic Disorders
 Depressive reaction


Manic depressive reaction, manic type
Manic depressive reaction, depressed type
Manic depressive reaction, other
DSM-II (1968)
Psychoses Not Attributed To Physical Conditions
 296 Major affective disorders
 Manic-depressive illnesses
Manic-depressive
 Manic-depressive
 Manic-depressive
 Manic-depressive
 Manic-depressive
depressed

illness, manic type
illness, depressed type
illness, circular type
illness, circular type, manic
illness, circular type,
US vs European Countries


Results from the landmark US/UK comparison study
(1972):
 Indicated that Bipolar disorder in the US was markedly
under-recognized as compared with European
diagnostic systems.
 Sparked an increased interest in developing
systematic/operational diagnostic criteria to improve
the reliability of diagnosis.
Operationalized diagnostic criteria were developed:
 Research Diagnostic Criteria
 DSM-II-R
Cooper, J. E., Kendall, R. E., Gurland, B. J., et al. (1972)
Developing a diagnostic criteria for children

First attempt to develop diagnostic criteria for manicdepressive psychosis in children was done by Anthony
and Scott (1960):
 Reviewed
28 papers (1884-1954) and created a 10
criteria for manic
 Only 3 in 60 cases met the developed criteria.
 These criteria basically eradicated the diagnosis of
manic depression in children, until subsequent studies
using Lithium appeared.
Anthony, E. J. & Scott, P. (1960)
Cont…
Developing a diagnostic criteria for children

Psychopharmacologic studies in the 1970s restored the concept
of childhood-onset bipolar disorder
Weinberg and Brumback (1976)
Davis (1979)
Coll & Bland, 1979 (CANADA)
1. Euphoric or irritable mood, AND
1. affective storms, defined as a loss
of control that is highly intense,
disruptive, and transient
1. Euphoria (either 1 or both [1-2] and 3
or more from 3-8)
a. Denial of problems or illness
b. Inappropriate feelings of well-being,
inappropriate cheerfulness
2. Three or more of the following,
which should reflect a change from
the child’s normal behavior:
a. hyperactive, intrusive behavior
b. push of speech
c. flight of ideas
d. grandiosity
e. decreased amount of sleep or
unusual pattern of sleep
f. distractibility
g. symptom duration of 1 month
2. significant family histories of
affective disturbances
2. Irritability and/or agitation
3. mental, verbal, and physical
hyperactivity
4. high level of distractibility
5. rapid talk or a ‘‘rapid progression
of interest’’
3. Hyperactivity, intrusiveness
4. Push of speech, garrulousness
5. Flight of ideas
6. Grandiosity (may be delusional)
7. Sleep disturbance (decreased sleep
and unusual sleep pattern)
8. Distractibility (short attention span).
Weinberg, W. A. & Brumback, R. A. (1976); Davis, R. E. (1979); Coll, P. G. & Bland, M. B. (1979)
DSM-III (1980) & DSM-III-R (1987)



“Manic-depression” substituted by “Bipolar”
Mania symptoms required to be present for a
week.
DSM-III-R Bipolar Disorder-Mixed, Bipolar
Disorder-Manic, Bipolar Disorder-Depressed,
Bipolar Disorder-Not Otherwise Specified, and
Cyclothymia.
DSM-IV & DSM-IV-R (1987)


DSM-IV to DSM-IV-TR - no major changes.
DSM-5

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Criterion A for manic and hypomanic episodes includes
an emphasis on changes in activity and energy as well
as mood.
Bipolar I, mixed episode eliminated; instead a new
specifier is included: “with mixed features”.
Anxious Distress Specifier (new)
NOS eliminated; instead “Other Specified Bipolar
and Related Disorder”
Aim 4
•
Review the literature on pediatric bipolar disorder
Bipolar Disorder Runs in Families…
BP Runs in Families…



One of the most hereditable psychiatric conditions as evidenced
by twins and other studies.
Higher concordances for BP among MZ twins, compared with DZ
twins; estimated heritability >80% (Craddock and Jones, 1999).
If one parent has BP, the risk of a child to have BP is between
10-25%; higher risk if both parents have BP (Goldstein et al., 2010;
Goldwin & Jamison, 2007).
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Risk increases during young adulthood (Birmaher et al., 2009) .
First-degree relatives of youth with BP are at higher risk of
developing BP…compared with families of health children or
children with MDD or ADHD (Geller et al., 2006)
Genetics

The study with the largest sample of pedigrees with
BP found:
Two chromosomal regions that meet stringent criteria
for genomewide significance (P<.05) on chromosomes
17q and 6q, and
 Three regions with suggestive evidence of linkage
(P<.10) on chromosomes 2p, 3q, and 8q.

 Sample:
1,152 individuals and 250 families; 10 sites.
Dick et al., 2003
Perinatal Risk Factors

Prenatal exposure to drugs
or birth complications,
increase the risk of having
a child with BP diagnosis
more than six-fold (Pavuluri et
al., 2006).
BP Brain Plasticity

Voxelwise meta-analysis, included 21 studies,
660 BD patients and 770 healthy control
subjects (Bora et al., 2010).
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Found gray matter deficits in BD, but only in two
regions (right fronto-insular and left anterior
cingulate).
Another studies reported cerebellar vermal size
was smaller in multiple-episode patients with BP
compared with first-episode and healthy
subjects (Del Bello et al. 1999, ; Mills et al. , 2005)
Cont…Brain Plasticity


Serum Brain-Derived Neurotrophic Factor (BDNF) levels were
significantly lower in both medicated and unmedicated
patients with bipolar disorder, compared with healthy controls
(P<0.0001).
 22 adults with bipolar disorder; medication-free,
 22 medicated adults with bipolar disorder, and
 22 healthy controls
Another study reported that BDNF levels were decreased only
in patients with bipolar disorder with late stage of illness.
(de Oliveira et al., 2009; Kauer-Sant’Anna et al., 2009)
Cont…Brain Plasticity

A study compared the progression of
abnormalities in white matter tract
integrity
 10 children with BP; 7 children at
risk for BP (first-degree relative
with BP); 8 healthy controls

Compared with health children,
children with BP exhibited
decreased fractional anisotropy
(FA) in right and left superior
frontal tracts, left orbital frontal,
and right corpus callosum (P<0.05)
Frazier, J. A. et al. 2007
Cont … Brain Plasticity
Frazier, J. A. et al. 2007
Cont … Brain Plasticity
Frazier, J. A. et al. 2007
Pediatric BD Onset
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> 50% of adults with bipolar report onset of
Sxs in childhood (Perlis et al., 2009).
Age 15 to 19 years old (Goodwin & Jamison, 2007).
Average age of onset in US is reported as
19.4 years versus 25.2 years in European
samples (Post et al., 2008).
However, BP has a lifelong onset; condition
could flourish in children and adults as old as
over 60 y/o
Prevalence


1996 – BP was the least frequent diagnosis (in-patient children),
BUT in 2004 – was the most frequent diagnosis (Blader & Carlson, 2007).
Based on a recent meta-analysis the rate of BP spectrum disorders
in youth is 1.8%, and for BP-I 1.2%; no significant rate difference
among UK and US (Van Meter, Moreira, Youngstrom, 2011).

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1-3% prevalence rate (Birmaher, 2013)
This is consistent with other studies (Stringaris et al., 2010;
Kozloff et al.,
2010)

Bipolar I and Bipolar NOS are more common in children than
Bipolar II (Birmaher et al., 2006)
Depression or Mania…
Which Emerges First?

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Depression seems to flourish first in youth, and the rate of
conversion to BP is 32%–50% (Ghaemi, 2008; Lewinsohn et
al., 2000).
This is higher than the conversion rate for adults (12.6% to
20%) (Akiskal et al., 1995; Ghaemi, 2008).
A prospective study followed 1,037 subjects from childhood
through age 26 (Kim-Cohen et al., 2003).
 Clinical interviews at age 11, 13, 15, 16, 18, 21, and 26.
 Diagnoses between ages 11 and 15 for those becoming
manic included: conduct disorder (38%), anxiety (35%), and
depression (20%).
Comorbidity

Bipolar disorder is often accompanied by other psychiatric
disorders (20%-80%).
 Disruptive Behavior Disorders
 ADHD
 Anxiety Disorders
 Substance Abuse Disorders
Children vs. Adolescents
C. ADHD and Oppositional Defiant Disorder > common
A. Conduct and Substance Abuse Disorders > common
Birmaher, 2013)
(Axelson et al., 2006)
Comorbidity – Anxiety Disorder

Common comorbidity in children and youth with BP:
 N=446, 7-17 y/o; BP 1=260, BP 2=32, BP NOS=154
 At least 1 lifetime AD (44%), most commonly separation
anxiety (24%), and GAD (16%)
 2 or more AD, nearly 20%
 AD predated the onset of BP; those with BP 2 were more
likely to have comorbid AD, longer duration of sxs, more
severe ratings of depression, and family hx of depression.
Sala, R. et al. (2010)
Comorbidity:
Conduct Disorder & Psychosis

CD
High rates of conduct disorder reported among youth with BP
(Weller et al., 2004).


42%-69% of clinic-referred youth with BP also had CD.
Psychosis
Co-occurrence rate is between 16% to 60% (Pavuluri et al., 2004)
 Delusional grandiosity, persecutory and religious delusions,
hallucinations, and thought disorder.
Comorbidity - ADHD


Most common comorbid condition among youths with BP;
studies report 60%-98% rates (Evans et al., 2005; Geller et al.,1998).
Uncommon in children with ADHD: (Hassan, A. et al., 2011)
 UK sample: n=200, 170 M, 30 F; 6-18 y/o, mean 11.15,
SD 2.95
 Only a 9-year-old boy, met diagnostic criteria for both
ICD–10 hypomania and DSM–IV bipolar disorder not
otherwise specified.
Main Features of BP in Youth

Tend to show mixed episodes rather than distinct episodes of
mania and depression. Tend to describe their mood episodes as
feeling “tired but wired”(Biederman et al., 2004).


Sample: 298 children with BP, none with clear-cut mania or
depressive episodes.
Tend to cycle fairly frequently from one mood state to the next.
Family members describe it as “mood swings” (Biederman et al., 2004;
Geller et al., 2000).

Onset – typically develops slowly over time.

Often show chronic and continuous mood problems.
Cost to Society and Individuals with BP

High rates of suicide, substance abuse, and neurocognitive deficits
associated with poor school functioning (Pavuluri et al 2005; Tolan and
Dodge 2005).


Risk of suicide attempt is increased by severe features of BP illness
and comorbidity (Goldstein et al., 2005).
Nearly one-half of individuals with bipolar disorder attempt suicide
(Jamison, 1999).

Worldwide, it currently accounts for 14 million years of healthy life
lost owing to mortality and disability, nearly as much as
schizophrenia (WHO, World Health Report 2002).
Does BP exist in younger children?


Duffy (2007) – argues lack of supporting evidence for the
hypothesis that BD, as currently defined, exists in very young
children.
 In some cases, there may be nonspecific prodromal
symptoms, including anxiety and sleep and cognitive
disturbances antecedent to the manifestation of BD.
BD often starts in adolescence with an episode of major
depression.
Duffy, A. (2007)
Aim 5
•
Present a new theoretical model for pediatric
bipolar disorder
Core Patterns of BP Disorder
Malhi, G. S. et al 2009
Stratified Model of BP Disorder
Malhi, G. S. et al 2012
Functional Neuroanatomy of BP:
A Consensus Model
Strakowski, S. M. et al (2012). Schematic of the proposed ventrolateral and ventromedial prefrontal networks underlying human
emotional control [adapted with permission from Oxford University Press (17)]. G. = globus; PFC = prefrontal cortex; OFC =
orbitofrontal cortex; BA = Brodmanns area.
Pediatric Bipolar Disorder Model
Nicasio, A. (2013)
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
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
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

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
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
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
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
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
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
Dick, D. M., Foroud, T., Flury, L., Bowman, E.S., Miller, M. J., Rau, N. L., Moe, P. R. , et al (2003). Genomewide linkage analysis of
bipolar disorder: a new sample of 250 pedigrees from the National Institute of Mental Health genetics initiative. Am J Hum Genet
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
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
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
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
Geller, B., Williams, M., Zimerman, B., Frazier, J., Beringer, L., Warner, K. L. (1998). Prepubertal and early adolescent bipolarity differentiate from ADHD by manic symptoms, grandiose delusions, ultrarapid or ultradian cycling. J Affect Disord, 51, 81-91,

Geller, B., Bolhofner, K., Craney, J. L., Williams, M., DelBello, M. P., Gundersen, K (2000). Psychosocial functioningin a prepubertaland
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
Geller, B., Tillman, R., Bolhofner, K., Zimerman, B., Strauss, N. A., Kaufmann, P. (2006). Controlled, blindly rated, direct-interview
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