Benjamin I.

Goldstein and Boris Birmaher

Isr J Psychiatry Relat Sci - Vol. 49 - No 1 (2012)

Prevalence, Clinical Presentation and Differential

Diagnosis of Pediatric Bipolar Disorder
Benjamin I. Goldstein, MD, PhD,1,2 and Boris Birmaher, MD2
1

Department of Psychiatry, Sunnybrook Health Sciences Centre, University of Toronto Faculty of Medicine, Toronto, Canada
Western Psychiatric Institute and Clinic, University of Pittsburgh School of Medicine, Pittsburg, Pennsylvania, U.S.A.

ABSTRACT
Background: Over the past 20 years, the evidence
regarding pediatric bipolar disorder (BP) has increased
substantially. As a result, recent concerns have focused
primarily on prevalence and differential diagnosis.
Method: Selective review of the literature.
Results: BP as defined by rigorously applying diagnostic
criteria has been observed among children and especially
adolescents in numerous countries. In contrast to
increasing diagnoses in clinical settings, prevalence in
epidemiologic studies has not recently changed. BPspectrum conditions among youth are highly impairing
and confer high risk for conversion to BP-I and BP-II.
Compared to adults, youth with BP have more mixed
symptoms, more changes in mood polarity, are more
often symptomatic and seem to have worse prognosis.
The course, clinical characteristics, and comorbidities
of BP among children and adolescents are in many
ways otherwise similar to those of adults with BP.
Nonetheless, many youth with BP receive no treatment
and most do not receive BP-specific treatment.
Conclusion: Despite increased evidence supporting the
validity of pediatric BP, discrepancies between clinical
and epidemiologic findings suggest that diagnostic
misapplication may be common. Simultaneously, low
rates of treatment of youth with BP suggest that
withholding of BP diagnoses may also be common.
Clinicians should apply diagnostic criteria rigorously
in order to optimize diagnostic accuracy and ensure
appropriate treatment.

BACKGROUND
Pediatric bipolar disorder: unicorn or ubiquitous?

The concept of children and adolescents suffering from

bipolar disorder (BP) is not a new one. However, whereas
case descriptions of pediatric mania have been available
for nearly a century (1, 2) it is only within approximately
the last two decades that rigorous research on this topic
has been conducted.1 Questions have been raised as
to reasons for increased attention to pediatric BP, and
simplistic conspiracy theories abound: an American
invention, a fabrication born of Big Pharma influence,
self-serving researchers seeking to create a niche (3).
Nonetheless, arguments against the existence of pediatric
BP have waned in recent years, and one hopes that the
quality of the research cited in this and other articles in
this edition of the Journal had a salutary effect.
More recently, prevalence and diagnostic accuracy
have become the primary controversies. Prior to the last
twenty years, childhood mania was considered exceedingly rare, and there are still settings in which this is the
case (4). This stood in contrast to findings that up to twothirds of adults with BP report child- or adolescent-onset
of impairing mood symptoms (5-7), and approximately
10% report childhood (<13 years of age) onset of mania
or significant manic symptoms (5, 7). An influential 1995
paper by Wozniak and colleagues indicated that 16% of
children presenting for treatment at a tertiary academic
child psychiatric clinic evidenced symptoms consistent
with mania, and raised the question of whether pediatric BP was being overlooked (8). By many accounts,
concerns regarding missed diagnoses of BP and underestimates of prevalence have been replaced with con1
For the purpose of this review, unless otherwise indicated, the term BP
encompasses all subtypes (I, II, cyclothymia, not-otherwise-specified [NOS]),
and the term pediatric refers to children and/or adolescents 19 years of age.

Address for Correspondence:

Dr. B. Goldstein, Department of Psychiatry, Sunnybrook Health Sciences Centre; 2075 Bayview Ave., FG53,
Toronto, Ontario, M4N-3M5, Canada [email protected]

Prevalence, Clinical Presentation and Differential Diagnosis of Pediatric Bipolar Disorder

cerns regarding misdiagnoses of BP and over-estimates

of prevalence. These concerns are in part owing related
to the possible over-use of mood-stabilizing medications.
Although prescriptions for mood-stabilizing medications for children have indeed increased dramatically
(9), unfortunately the majority of adolescents with BP
do not access treatment for their illness (10). Similarly,
although concerns have been raised regarding increased
use of the BP diagnosis among youth (11), the number
of youth who receive diagnoses of BP in clinical settings
falls far short of what would be expected based on the
population prevalence of BP (12).
Pediatric BP diagnosis presents a challenging dialectic. Withholding of diagnoses and treatment of BP from
patients who truly have BP presents substantial morbid risks, including suicidality and marked functional
impairment (13, 14). However, unnecessary diagnoses
and unnecessary exposure to mood-stabilizing medications risk unduly invoking concerns about a life-long
illness, pre-empting psychosocial treatments, delayed
and/or suboptimal pharmacological treatment of other
psychiatric conditions such as major depressive disorder (MDD) or attention-deficit hyperactivity disorder
(ADHD), and significant physical risks (15). As such,
one focus of this review is on summarizing recent literature that can inform considerations regarding accurate diagnoses of individual children and adolescents
with and without BP. Another focus of this review is on
highlighting various demographic, clinical, and familial
characteristics that are salient to the diagnosis, monitoring, and treatment of youth with BP.
PREVALENCE
The prevalence of BP among youth varies depending
on how and where the sample is ascertained and the
methods used to diagnose BP. Moreno and colleagues
reported a 40-fold increase in visits for BP among youth
in managed care between 1994-1995 and 2002-2003
(11). However, diagnoses were determined via billing
codes, which are of uncertain reliability and which may
be influenced by external factors such as up-coding in
order to ensure that children receive sufficient mental
health services. That is, clinicians may diagnose pediatric BP because treatment for this diagnosis is often
subject to fewer constraints within managed care organizations, whereas diagnoses such as conduct disorder
often have comparatively less allocation of resources or
have low expenditure limits relative to BP. Moreover,
4

the estimated change was likely inflated by counting

multiple visits by the same patients, and frequent use
of health services is common in BD (16). In addition,
the baseline proportion of psychiatric visits for pediatric
BD in 1994-5 was 0.42%, meaning that fewer than 1 in
200 children and adolescents receiving psychiatric care
carried a diagnosis of BP. Over a similar time period,
rates of hospital discharges of children with a primary
diagnosis of BD increased from 1.3 per 10,000 in 1996
to 7.3 per 10,000 in 2004 (17). Therefore, these large
relative increases may be accentuated by what some
would describe as an exceedingly low initial base rate,
particularly in light of the fact that child- or adolescentonset is common among adults with BP (5-7).
The recent National Comorbidity Survey ReplicationAdolescent Supplement (NCS-A) found that approximately 1% of adolescents have strictly defined BP-I and
if subsyndromal symptoms of BP are included, the rates
increase to approximately 6% (18). The prevalence of
BP-I or -II in the NCS-A doubled between ages 13-14
and 17-18 years of age (12). Previous epidemiologic
data from the Oregon Adolescent Depression Project
(OADP) nearly 20 years prior indicated a combined
prevalence of 5.7% for full- and sub-threshold BP (0.1%
BP-I) among adolescents (19). The 2002 Canadian
Community Health Survey included a proxy for BP
comprising episodes with sufficient symptoms and severity to be characterized as mania, but with the exception
that duration of symptoms did not have to reach a full
week (20). Similar to the NCS-A finding of increasing
prevalence with age, that study found a nearly two-fold
increased prevalence between adolescence (15-18 years,
2.1%) and young adulthood (19-24 years, 3.8%). A recent
meta-analysis of epidemiological studies of pediatric BP
included 16,222 youths (7-21 years) from 12 studies (6
from U.S., 6 international) conducted between 1985
and 2007 (21). The mean prevalence of BP spectrum
disorders was 1.8% (95% confidence interval [CI] 1.1%3.0%), and the mean prevalence of BP-I was 1.2% (95%
CI 0.7%-1.9%). Rates of BP spectrum disorders in studies
of adolescents only (12 years and older) averaged 2.7%
(95% CI 1.6-4.6%), higher than the overall prevalence in
studies combining children and adolescents (1.8%, 95%
CI 1.1-3.0%). Methodological differences may explain
in part the variability in prevalence. For example, the
OADP found only 0.1% prevalence of BP-I, contrasting
other epidemiologic samples with rates of up to 2-3% of
BP-I among adolescents (22, 23). The OADP enrolled
students from the high-school setting (vs. households)

Benjamin I. Goldstein and Boris Birmaher

and did not interview parents, either of which may have

contributed to the low BP-I prevalence, although other
factors may also contribute. Perhaps surprisingly, the
mean rate of BP in the 6 studies from the U.S. (1.7%)
did not differ from the mean rate in the 6 studies from
outside the U.S. (1.9%), this despite the fact that two U.S.
studies included BP-spectrum conditions other than BP-I
and BP-II and therefore had the highest prevalence (18,
19). Importantly, and in contrast to temporal trends in
clinical diagnoses, there was no evidence of increasing
prevalence of BP spectrum disorders over time. In summary, there has been stable prevalence over time of youth
BP spectrum (particularly adolescent BP) as ascertained
by rigorous semi-structured interviews in unselected
epidemiologic sample, where there has been increased
prevalence of youth BP in clinical settings. Explanations
for this phenomenon include higher rates of treatmentseeking for pediatric BP over time, or insufficiently
stringent application of diagnostic criteria in clinical
settings. At least in Canada and the U.S. the former
explanation does not appear likely, as rates of treatmentseeking are disturbingly low (discussed below) (10, 18,
20). Therefore, strategies for addressing false positive
diagnoses of BP among youth likely need to be informed
by a better understanding of what is driving the excess
of clinical diagnoses. Similarly, strategies for addressing
untreated BP in the community need to be informed by
a better understanding of barriers to accurate diagnoses
and appropriate treatment. Thus far, rigorous epidemiologic studies have focused on adolescents, such that little
is known regarding the epidemiology pre-adolescent
BP. Pharmaco-epidemiologic studies that have examined pre-adolescent BP have not employed standardized assessments. Although these studies can address
billing diagnoses, they cannot address questions about
the epidemiologic prevalence of rigorously defined BP.
Given that the prevalence of BP was substantially higher
among older adolescents vs. younger adolescents in the
NCS-A, it is possible that the prevalence of BP among
pre-adolescent children is even lower. However, definitive
conclusions are deferred pending large epidemiologic
studies of children.
CLINICAL PRESENTATION
Manic/hypomanic Symptoms

The Diagnostic and Statistical Manual of Mental

Disorders, Fourth Edition, Text Revision (DSM-IV-TR)
symptom criteria for BP are the same for children, ado-

lescents and adults. However, as discussed below there

are developmental differences in the presentation of
mania/hypomania in youth. Symptoms of mania are the
hallmark of BP. Either elation/euphoria or irritability
are required. Other symptoms include grandiosity, distractibility, decreased need for sleep, increased amount
and/or rate of speech, increased rate of thoughts or
rapid flow of expressed ideas, increased involvement
in risky pleasurable activities, increased motoric activity or restlessness, and increased productivity or goaldirected activity. Because silly, rambunctious, and/or
impulsive behavior often characterizes childhood and
adolescence, it is important particularly for hypomania
to be able to distinguish normal childhood behavior
from psychiatric symptoms. In order to be considered
a pathological symptom, elation must be inappropriate
to context and associated with a change in functioning, and the same applies for grandiosity. Beyond these
general considerations, it is central to accurate diagnoses to determine whether a given symptom is pathological for an individual child in a particular situation
or setting. Take for example a child who has clear-cut
ADHD, who usually has significant insomnia, and who
is consistently silly and somewhat defiant. If this child
on a given day is hyperactive, silly, distractible, and defiant with his teacher, that would not comprise a distinct
mood-related change from baseline behavior. But take
for example a child who does not have ADHD, who is
consistently agreeable and well-behaved, and who is
generally subdued with regard to expression of affect.
If this child suddenly presents as hyperactive, silly, distractible, and defiant for several days, then it becomes
important to determine whether these are symptoms
of hypomania or are better explained by other factors
(e.g., stress, substance use). In terms of sleep specifically, it is critical to parse insomnia from reduced need
for sleep. The former is associated with difficulty rousing whereas the latter may in fact be characterized by
early waking and intact alertness despite substantially
fewer hours of sleep. Case-based descriptions of how
children with mania differ from healthy children and
from adults with mania are available (24). Because irritability is a symptom common to multiple psychiatric
disorders (e.g., MDD, generalized anxiety disorder,
oppositional defiant disorder), one approach that has
been taken in order to optimize diagnostic specificity is to require elation or grandiosity (25). However,
DSM-IV-TR does not necessitate this, and indeed studies from different research groups have questioned the
5

Prevalence, Clinical Presentation and Differential Diagnosis of Pediatric Bipolar Disorder

necessity of elation/euphoria (26, 27). Findings from

the COBY study, for example, suggest that in about 80%
of the cases both elation and irritability are present during the most severe symptomatic episodes among BP
youth and, with few exceptions, the course, comorbidity and family psychiatric history of youth with solely
irritable mania/hypomania does not substantially differ
from that of youth with solely elation or those with both
elation and irritability (27).
Manic/hypomanic Episodes

The diagnosis of bipolar I disorder (BP-I) is given when a

patient has had at least one clear manic or mixed manic
(mania concurrent with depression) episode in his/her
lifetime. An episode is a period of time during which
symptoms comprise a noticeable change from that persons baseline, whether that baseline is one of health or
one that is affected by symptoms of a comorbid condition
such as anxiety or attention-deficit hyperactivity disorder (ADHD). If the requirement for episodes were to be
waived, this raises concerns about misdiagnosis, particularly among youth with ADHD which has multiple
over-lapping symptoms. To count as a manic episode,
symptoms must cause marked functional impairment and
must last at least one week or necessitate hospitalization.
A diagnosis of bipolar II disorder (BP-II) is given when
a patient has had at least one hypomanic episode (similar symptoms, but absent major functional impairment,
psychosis, or the need for hospitalization) and one major
depressive episode in his/her lifetime. Other BP-spectrum
diagnoses are less clearly defined, and include cyclothymia (numerous brief depressive and hypomanic intervals
without prolonged recovery for 1 year) and BP not otherwise specified (BP-NOS; described below). There is substantial consensus that episodes are one of the hallmarks
of BP and that phenotypes characterized by chronic
irritability and ADHD, absent episodicity, often are not
consistent with a diagnosis of BP (28, 29).
Bipolar Disorder Not Otherwise Specified
and Subthreshold Bipolar Disorder

Although BP is classically thought of in terms of the

acute manic episodes of BP-I, there is convergent evidence from adolescent and adult epidemiologic studies
that subthreshold BP or BP-NOS (henceforth BP-NOS)
is a more common presentation (18, 30). In addition,
there is also convergent evidence from clinical and epidemiologic studies that BP-NOS is clinically impairing, and clinical studies suggest further that BP-NOS is
6

familial and predictive of conversion to BP-I and BP-II

(18, 19, 30-33). However, in comparison with BP-I or
II, DSM-IV criteria for BP-NOS are less clearly defined.
American Academy of Child and Adolescent Psychiatry
(AACAP) practice parameters advise as a clinical guideline that BP-NOS should be used to describe youth with
brief hypo/manic episodes lasting hours to less than four
days, or describe youths with chronic manic-like symptoms that comprise their baseline level of functioning
(34). Because of an important need for a clearer definition of what comprises BP-NOS, the COBY study offered
an operationalized definition requiring that symptoms
must be evident for a minimum of four hours in a day on
a minimum of four separate lifetime days in order to be
classified as BP-NOS (35). These children have very similar symptoms, comorbidities, and family histories to children with BP-I (31, 35). Moreover, 45% of these children
will go on to meet strict criteria for BP-I or BP-II within
five years, and nearly two-thirds of BP-NOS youth with
family history of BP convert to BP-I or BP-II (36). Even
in epidemiologic samples, sub-threshold episodic BP is
associated with substantial functional impairment and
comorbidity, and rates of treatment use that approach that
of BD (19, 33). However, the Longitudinal Assessment of
Manic Symptoms (LAMS) study suggests that despite the
fact that symptoms of mania are evident in approximately
40% of children (6-12 years of age) attending outpatient
psychiatric clinics, most youth presenting with these
symptoms (75%) do not meet the criteria for BP-I, -II, or
-NOS, highlighting the importance of ensuring minimal
symptom number and duration criteria are met before
assigning a BP-spectrum diagnosis (37).
AACAP vs. NICE

The DSM-IV-TR criteria for manic and hypomanic episodes do not differ for children and adolescents, although
clinical judgment is required to allow for developmentally-sensitive approaches to inquiring about and classifying symptoms. The AACAP practice parameters advise
that these unaltered criteria should be employed with
children and adolescents, and allow for use of BP-I, BP-II,
or BP-NOS among children and adolescents (34). In contrast, the U.K.s National Institute for Health and Clinical
Excellence (NICE) clinical guideline for BP suggests
diagnostic modifications for children and adolescents
(38). The guideline acknowledges that BP-I can be diagnosed in pre-pubertal children, but requires that euphoria is present and does not allow irritability as a core
diagnostic criterion. For adolescents, the NICE guide-

Benjamin I. Goldstein and Boris Birmaher

line indicates that irritability can be helpful in making a

diagnosis if it is episodic, severe, results in impaired function and is out of keeping or not in character (p. 56),
but should nonetheless not be used as a core diagnostic
criterion. According to NICE, use of the BP-II diagnosis is not advised among children or adolescents, with
the exception of older or developmentally advanced
adolescents, in which case adult criteria should be used.
Further elaboration of international differences in rates of
BP and in diagnostic criteria can be found in the article
by Carlson and Dyson in this journal.
Course and Outcome

Information regarding the clinical course of adolescent

BP was until recently limited to relatively small studies.
However, larger studies have yielded crucial longitudinal
data (31, 39, 40). The course of adolescent BP following
first hospitalization for mania is characterized by both
recovery and recurrence (40). Geller and colleagues
recently published eight-year follow-up data regarding
a cohort of pre-pubertal children and early adolescents
with BP-I, and found that subjects spent 60% of the time
symptomatic (either in full-threshold mood episodes
or with clinically significant sub-threshold symptoms),
and continue experiencing mood episodes in youngadulthood (39). The COBY study, the largest of its kind
(N=413), suggests that in many ways the longitudinal
course of youth BP-I mirrors that of adults: most experience episodic recovery and recurrences; depression is the
prevailing polarity; and subsyndromal symptoms, particularly of the mixed and depressive type, predominate
(31). However, compared to adults with BP-I, youth with
BP-I spend more time with syndromal and clinically significant subsyndromal symptoms (59% vs. 47%), spend
more time in mixed episodes, and have far more changes
in polarity and in symptomatic status (41). Across subtypes of BP in COBY (including types I, II, and NOS),
this illness is characterized by recovery (eight contiguous
weeks of remission) and recurrences (31). During four
years of prospective follow-up, participants spent 16.6%
(2 months/year) of the time in full-threshold mood episodes and 41.8% (5 months/year) of the time suffering
from sub-threshold but clinically significant mood symptoms. Changes in mood polarity were common, and 51%
had 5 annual polarity changes (note: polarity changes
are not always part of full-threshold mood episodes, so
that this is not synonymous with DSM-IV rapid-cycling).
Finally, COBY provides validation for the operationalized definition of BP-NOS described above. Nearly 40%

of children and adolescents with BP-NOS convert to

BP-I or BP-II during prospective follow-up, thus demonstrating that in addition to significant episodicity and
symptomatic impairment, the COBY-operationalized
diagnosis of BP-NOS frequently forebodes more classical BP-I and BP-II (31, 35). Whereas studies to date
demonstrate diagnostic continuity of pediatric BP (31,
39, 40), there is evidence from adults of diagnostic conversion over time, most commonly to primary psychotic
disorders (42). Longer follow-up of extant pediatric BP
cohorts will be needed to determine the rate of conversion to primary psychotic disorders.
Bipolar Disorder in School-age
Children vs. Adolescents

Relatively few studies have directly compared the

symptoms and clinical presentations of children with
BP to those of adolescents. One study compared children with BP to adolescents with childhood-onset BP
and adolescents with adolescent-onset BP, finding that
euphoria was more common among adolescents with
childhood-onset BP, whereas irritability was least common among adolescents with adolescent-onset BP (43).
Childhood-onset BP was associated with greater severity of increased energy, and this was observed among
children with BP as well as among adolescents with
childhood-onset BP. Findings from some of the larger
cohorts of BP youth suggest no significant differences
in symptoms between children and adolescents with BP
(25, 44). Several studies have found that the prevalence
of ADHD and/or ODD may be higher among children
versus adolescents with BP (45, 46). Recent findings
based on the National Hospital Discharge Survey suggest that children with BP are most likely to have been
in a mixed episode (32%), followed by adolescents
(25%) and adults (13%) (17).
This topic was also examined comprehensively in
the COBY study. Familial loading of psychopathology
may be greater in childhood-onset versus adolescentonset BP (47). Adolescents were more likely to have
had a lifetime major depressive episode, and were more
likely to have had depression as the initial polarity of
illness, whereas children were more likely to have first
presented with manic/hypomanic symptoms. Manic
and depressive symptom severity was greater among
adolescents vs. children, and this was true also for the
severity of most individual symptoms (48). Comorbid
conduct disorder and comorbid SUD were more common among adolescents than among children, comor7

Prevalence, Clinical Presentation and Differential Diagnosis of Pediatric Bipolar Disorder

bid ADHD was more common among subjects with

childhood-onset ADHD, and panic disorder was most
common among adolescents with adolescent-onset BP.
Bipolar Disorder in Preschool-age Children

In comparison to the topic of BP among school-age

youth, BP among preschoolers is perhaps more controversial and has been the subject of comparatively little
research to date. One of the few minimal standard
recommendations in the AACAP practice parameter
for BP is that caution is advised before diagnosing preschoolers with BP, due to uncertain validity (34). That
said, several groups have reported on small samples
of preschoolers who present with symptoms of hypo/
mania (49-54). In one cases series, preschool mania was
consistently characterized by strong family history of
mood disorders and by antecedent ADHD (54). Perhaps
surprisingly, descriptions of preschoolers with BP have
often included classical features. For example, specific
symptoms of mania such as elation and grandiosity
have been prominent in several reports, and the course
of illness in a series of 26 patients was significant for
high recovery and relapse rates (i.e., episodicity) (49, 51,
55). One study included 26 preschoolers with BP as well
as comparison groups of preschoolers with depression,
disruptive behavior disorders, and no psychiatric disorders (50). Even after controlling for comorbid ADHD,
preschoolers with BP demonstrated significantly greater
functional impairment than did preschoolers with disruptive behavior disorders or healthy preschoolers.
Clearly, the diagnosis of BP in preschoolers should
be used judiciously, and prevalence estimates in this
age range are not presently available. Extant challenges
in the accurate diagnosis of BP in school-age children,
particularly those related to developmentally sensitive
symptom ascertainment, are further accentuated in the
preschool age group. However, compelling descriptions
of directly observed manic symptoms have been published. Kraepelin referred to the case of a 5-year-old
boy with mania (2) p.167). Poznanski and colleagues
described the case of a 4-year-old child with maternal history of BP who presented with recurrent brief
hypomanias against a background of consistent ADHD
symptoms (56). In that case report, the inclusion of parent and teacher reports, the nuanced behavioral descriptions including developmental context, and the care
taken to demonstrate differences from the usual ADHD
symptoms together make a compelling argument for
preschool BP. In our view, BP is likely less common
8

among preschoolers than among school-age children

and adolescents, however recognition of how symptoms
of BP manifest in a preschooler can provide a framework
for when to include BP on the differential diagnosis in
such young children.
Suicidality

Similar to adults, BP among youth is a potent risk factor

for completed suicide (57-59). Whether in community
or clinical samples, approximately 3 in 4 youth with BP
endorse lifetime suicidal ideation (19, 35). The lifetime
prevalence of suicide attempts among youth with BP
varies across studies, but appears to be at least 20% and
sometimes nearly 50% (13, 60, 61). Epidemiologic findings from the U.S. indicate that the lifetime prevalence of
suicide attempts among adolescents with BP spectrum
disorders (44%) was double that of adolescents with
MDD (22%) which was in turn far greater than that of
healthy adolescents (1%) (19). Moreover, adolescents with
BP in this sample make more attempts, make more lethal
attempts, and are younger at the time of their first attempt.
The question arises as to which youth among those
with BP are at greatest risk for attempting suicide. The
prevalence of suicide attempts appears to be greater
among older youth (13, 62). With the exception of
older age, findings from the COBY study do not suggest
any demographic predictors of suicide attempts (13).
Interestingly, rates of suicide attempts did not significantly differ across BP subtypes. Clinical predictors of
lifetime suicide attempt include mixed episodes, psychosis, psychiatric hospitalization, comorbid panic disorder,
comorbid SUD, poor family functioning, family history
of suicide attempt, history of physical or sexual abuse,
suicidal ideation, and non-suicidal self-injury (13, 62).
Impairment in Functioning and Quality of Life

The NCS-A characterized impairment as some, a lot,

or extreme (12). Fully 90% of adolescents with BP
endorsed severe impairment, whereas this was true for
74% of adolescents with MDD, 49% of adolescents with
disruptive behavior disorders, and 26% of adolescents
with anxiety disorders. A recent study found lower
quality of life among youth BP than among youth with
other medical and psychiatric disorders (14). Quality of
life in important domains such as family, friends, and
school was especially reduced compared to other youth,
and was even poorer than among youth with MDD.
Comorbid anxiety disorders and disruptive behavior
disorders, especially in the context of maternal mood

Benjamin I. Goldstein and Boris Birmaher

disorders, appear to be associated with worse family

functioning among youth with BP (63).
Medical and Mental Health Service Utilization

Epidemiologic findings from studies in the U.S. and

Canada suggest that under-treatment of BP among adolescents is problematic, as only 45-55% of adolescents with
BP report accessing any mental health services in their
lifetime (19, 20). Treatment rates are especially poor for
adolescents with BP when disorder-specific services are
examined, rather than any overall mental health services.
Only 22.2% of adolescents with BP-I or II in the NCS-A
report accessing treatment in their lifetimes specifically
targeting BP (10). By comparison, 59.8% of adolescents
with ADHD and 39.4% of adolescents with MDD or dysthymia reported lifetime use of services targeting those
disorders. However, findings based on health insurance
claims indicate that those adolescents with BP who do
access treatment incur markedly increased behavioral
health costs than adolescents with other mood disorders
or non-mood disorders (16). Youth diagnosed with BP
do often access treatment for ADHD, depression, and
disruptive behavior (64). It is possible that some treatments for these problems may benefit youth with BP (e.g.,
cognitive-behavioral therapy, family therapy). However,
failure to integrate the BP diagnosis could lead to suboptimal psychosocial treatment, which relies on appropriate
psycho-education (e.g., misinterpreting manic symptoms
as behaving badly), or to potentially mood-destabilizing
pharmacologic interventions (e.g., stimulants, anti-depressants), in addition to prolonging the delay to appropriate
treatment. Unfortunately, it is precisely the adults with
youth-onset BP who report both the most prolonged
delays in treatment for BP and most severe courses of illness (historically and prospectively) (6, 7, 65, 66).
Psychiatric Comorbidity

Comorbidity is the norm in BP, and the majority of adults

with BP have 2 other psychiatric conditions, most commonly anxiety disorders and substance use disorders
(SUD) (30). A meta-analysis of children and adolescents
with BP found that ADHD (62%) was the most common
comorbidity, followed by oppositional defiant disorder
(ODD; 53%), anxiety disorders (27%), conduct disorder
(CD; 19%), and SUD (12%) (67). Comorbidities such as
eating disorders and pervasive developmental disorders
occur less commonly. ADHD appears to be more common among children with BP, whereas panic disorder,
conduct disorder, and SUD appear to be more common

among adolescents with BP (48). Studies suggest that

comorbidities may exacerbate the course and outcome of
BP. For example, comorbid ADHD has consistently been
associated with decreased response to mood-stabilizing
medications, and this effect is especially pronounced
among adolescents (vs. children) and among those with
BP-I (68). Comorbid anxiety disorders have been associated with greater depression severity, and with reduced
efficacy of antimanic treatment (69, 70). Finally, comorbid SUD are associated with concerning outcomes such as
medication non-adherence, suicide attempts, legal problems, and teenage pregnancy and abortion (40, 71). The
impact of comorbidity, particularly ADHD (72), on treatment decisions is elaborated elsewhere in this collection.
Medical Comorbidity

Medical comorbidity is a major concern in BP.

Cardiovascular disease is both exceedingly prevalent
and premature among adults with BP, leading to excessive cardiovascular mortality (73). Although psychiatric
medications are associated with metabolic disturbances,
the association between BP and cardiovascular disease was
observed prior to the advent of modern medications (2).
Metabolic syndrome components (dyslipidemia, hyperglycemia, hypertension, and obesity) are also exceedingly
prevalent among adults with BP, and are associated with
a more pernicious course of illness, including increased
functional impairment, suicide attempts, and manic and
depressive episodes (74). Recent findings suggest that
despite their young age, children and adolescents with BP
may also incur increased risk of medical comorbidities.
Between 28-36% of youth with BP suffer from multiple
medical conditions, whereas this is true for only 8% of
youth with other psychiatric disorders combined (75, 76).
Obesity, hypertension, and diabetes are highly prevalent
and often precede BP, and use of specialty cardiology services is doubled. Correlates of overweight/obesity among
youth with BP include history of physical abuse, comorbid
SUD, psychiatric hospitalizations, and exposure to multiple classes of mood-stabilizing medication (77). Migraine,
asthma, and neurological conditions such as epilepsy may
also co-occur disproportionately with BP (75, 76).
Differential Diagnosis

The primary differential diagnosis of pre-adolescent BP

is ADHD. The overall rate of comorbid ADHD among
studies of pediatric BP (62%) (67) is problematic because
the extent of overlapping symptoms of ADHD presents
unique diagnostic challenges. Methods for distinguishing
9

Prevalence, Clinical Presentation and Differential Diagnosis of Pediatric Bipolar Disorder

BP from the more prevalent ADHD have been described

previously. The two primary distinguishing features of
BP are the discrete episodes of BP and the distinguishing
symptoms of mania (78). Different approaches have been
taken to delineate BP (with or without ADHD) from
ADHD. One approach is to double count symptoms.
That is, if a child is highly distractible and hyperactive,
then these two symptoms would be counted toward a
diagnosis of ADHD as well as toward a manic episode
(i.e., BP). Proponents of this strategy argue that it is
impossible to reliably attribute the cause of one symptom to one disorder over another. An advantage of this
strategy is that it requires less clinical discretion and
judgment, which may enhance reliability if at the expense
of validity. The primary disadvantage of this approach
is that it may sacrifice specificity, leading to numerous
diagnoses of BP among youth with ADHD. An alternative approach is to endeavor to determine whether
any overlapping symptoms are clearly exacerbated in
the context of mood disturbance. That is, if ADHD is
present, overlapping symptoms such as distractibility
or hyperactivity are only counted toward a diagnosis of
mania or hypomania if they intensify concurrently with
episodes of elation or irritability. The same strategy can
be applied to diagnoses of generalized anxiety disorder
or oppositional defiant disorder, other comorbidities that
include more chronic symptoms that overlap with manic
symptoms. For example, a child with generalized anxiety
disorder consistently experiences irritability, impaired
concentration, and restlessness. Therefore, in order to
meet criteria for mania or hypomania, there would need
to be a distinct exacerbation in these symptoms, as well
as at least two additional symptoms of mania.
One symptom that generates substantial diagnostic
uncertainty is irritability. The DSM-IV-TR indicates that
irritability is a core symptom of mania and hypomania.
Provided that 4 other symptoms of mania are present, an
episode of increased irritability even in the absence of elation is sufficient to warrant a diagnosis of mania or hypomania. Irritability can pose diagnostic challenges among
youth because it is also a diagnostic criterion for major
depressive episodes among youth, generalized anxiety
disorder, and oppositional defiant disorder. Irritability
also frequently accompanies pervasive developmental
disorders, conduct disorder, ADHD, substance use disorders, and obsessive compulsive disorder. As such, it is
important to determine whether mania or hypomania is a
likely factor in explaining irritability or whether irritability is better explained in a given patient by other forms
10

of psychopathology including several of those described

above. It is crucial for the purpose of differential diagnosis to clarify whether there are episodes of irritability, or
episodic unequivocal exacerbations in baseline irritability,
that are associated temporally with other manic symptoms. Irritable mania/hypomania in the absence of elation
was a relatively uncommon scenario in the COBY study,
however it is important to note that the 10% of patients
with this presentation had demographic, clinical, and
familial characteristics that were highly comparable to
subjects whose hypo/manic episodes include elation
(27). In summary, the keys to interpreting irritability with
respect to a possible BP diagnosis are the determination
of episodicity and of temporal contiguity with sufficient
other symptoms of mania.
The concept of chronic, non-episodic irritability is
central to differential diagnosis, and has led to the consideration of a new proposed diagnosis for the upcoming DSM-V, Temper Dysregulation Disorder with
Dysphoria (TDD) or more recently Disruptive Mood
Dysregulation Disorder (DMDD), based on research
regarding severe mood dysregulation (SMD; severe,
nonepisodic irritability with hyperarousal symptoms),
which was earlier described as broad phenotype BP
(29, 79). However, children with SMD (of whom 86%
have ADHD, 85% have ODD and 75% have both) (29),
have different symptoms, comorbidities, family histories, neuropsychology, and neurobiology from children
with BD-I (29)(80-83). By definition, these children do
not have distinct hypomanic/manic episodes. Use of
a BP diagnosis in these cases is of questionable value
because of the cross-sectional differences noted above,
and because SMD-like phenotypes do not appear to be
particularly predictive of future BP (29).
Familial High-Risk for Bipolar Disorder

BP is among the most highly familial of psychiatric illnesses. Twin studies suggest that heritability of BP is
approximately 0.7-0.8, whereas heritability for MDD
is approximately 0.3 (84). Evidence from bottom-up
(children as probands) studies suggests that the prevalence of BP is increased among relatives of children and
adolescents with BP when compared to healthy children
or those with other psychiatric illnesses such as ADHD
or anxiety disorders (85, 86). In addition, multiple
studies have examined for the presence of psychiatric
disorders among the offspring of parents with BP, and
these studies consistently demonstrate increased risk of
mood disorders among offspring (87, 88). Recent find-

Benjamin I. Goldstein and Boris Birmaher

ings from the large-scale Pittsburgh Bipolar Offspring

Study (BIOS) indicate that offspring of parents with
BP (N=388; mean age 11.9 years) have approximately
a 13-fold increased risk (10.6% vs. 0.8%) compared to
control offspring (N=251) of having bipolar spectrum
disorders (BP-I, -II, or NOS) (32). Although most
cases were BP-NOS, the rate of BP-I among high-risk
offspring (2.1%) was significantly higher than among
control offspring (0%). Of note, 75.6% of BP offspring
who had any bipolar spectrum disorder had onset prior
to age 12. Preliminary analysis showed that after 10
years of follow-up rates of BP in the offspring of the parents with BP were 20-fold greater compared to offspring
of controls (89). Recent findings in a large sample of
adolescent offspring (mean age 16.7 years) of parents
with BP found that 8.5% had a bipolar spectrum disorder, and 4.3% had BP-I specifically (90). Some studies
have found lower rates of bipolar spectrum disorders
than those described above (91, 92), and possible reasons for this discrepancy include nationality, age of
subjects at intake, sample size, and interpretation of
symptoms among children. Nonetheless, approximately
90% of school-aged offspring of parents with BP do not
suffer from BP, raising the question of who among these
offspring is at especially increased risk. Risk factors for
BP among school-aged offspring may include antecedent anxiety disorders and disruptive behavior disorders,
and the risk of BP may be increased if both parents have
BP (93). Although odds ratios are greatest for bipolar
spectrum disorders, offspring of parents with BP also
incur increased risk for anxiety disorders, depressive
disorders, and disruptive behavior disorders.
Clinical High-Risk for Bipolar Disorder

Several studies suggest that pre-natal and peri-natal risk

factors, as well as stressful life events, may contribute to
risk for BP, albeit that the data are more tenuous than
those relating to schizophrenia and major depression,
respectively (94, 95). Several psychiatric disorders may
commonly precede the onset of BP. The incidence of
BP among clinically-ascertained children and adolescents with MDD appears to be approximately 15-20%
within 3-6 years, with higher rates generally observed
among inpatient samples and in studies with longer
follow-up. Risk factors for BP among adolescents with
depression include rapid-onset of depression, familial
loading of mood disorders, the presence of psychotic
features, and the presence of treatment-emergent mania
(96). Epidemiologic data suggest that anxiety disorders

and oppositional defiant/conduct disorders may also be

strongly predictive of subsequent BP, although in these
cases clinical risk factors for conversion to BP have yet
to be identified (23). Perhaps surprisingly, it is not as
clear that ADHD is a risk factor for BP, particularly in
the absence of other comorbidities (97).
Summary
Taken together, the literature to date suggests several
conclusions. BP as defined by rigorously applying diagnostic criteria has been observed among children and
more commonly in adolescents in numerous countries.
The prevalence of clinically meaningful BP-spectrum
conditions is greater than that of BP-I, and, importantly,
BP-NOS among youth is often a gateway to BP-I or
BP-II. Substantially increased use of the BP diagnosis has
been observed in clinical but not epidemiologic studies,
potentially implicating non-adherence with diagnostic
criteria. The course, clinical characteristics, and comorbidities of BP among children and adolescents are in
many ways similar to those of adults with BP, and continuity of pediatric BP into adulthood has recently been
demonstrated. Together with family studies, treatment
studies and neurobiological studies, these data provide
increased support for the validity of pediatric BP. The
challenge of how to reduce the disparity between clinical
and epidemiologic findings remains, and this may be in
part due to the difficulties ascertaining symptoms such
elation and grandiosity in children. The complexity of BP,
particularly the high rate of comorbidity with diagnoses
that include overlapping symptoms, is also likely contributory. Up to 55% of youth with BP receive no treatment
whatsoever, and rates of diagnosis-specific treatment lag
well behind those among youth with ADHD and MDD.
Redoubled effort is warranted to ensure that clinicians
screen for and treat BP among youth when indicated, and
that diagnoses of and treatment for BP are only given
after systematically ascertaining the necessary symptoms
and episodes of mania and hypomania. In addition, clinically applicable biomarkers and psychometrically sound
screening strategies summarized elsewhere in this edition
of the Journal offer hope that diagnostic accuracy will
improve further in coming years.
Key Points
Billing diagnoses of pediatric bipolar disorder have
increased dramatically, whereas epidemiologic stud11

Prevalence, Clinical Presentation and Differential Diagnosis of Pediatric Bipolar Disorder

ies employing standardized interviews suggest relatively stable prevalence.

There is increasing consensus that pediatric mania or
hypomania can be euphoric, irritable, or both, provided that sufficient other symptoms are present, and
that symptoms track together episodically.
Similar to bipolar I disorder, sub-threshold bipolar
disorder (e.g., bipolar disorder not otherwise specified) is associated with suicidality, significant functional impairment, and substantial comorbidity. If
defined by an episodic course, nearly half of cases
sub-threshold bipolar disorder convert to bipolar I
or II disorder over five years.
The course of pediatric bipolar disorder is characterized by recovery, recurrence, and persistence into
young adulthood.
Compared to the course of adult bipolar disorder,
the course of pediatric bipolar disorder is characterized by a greater proportion of time symptomatic, a
greater proportion of time in mixed states, and more
frequent polarity switches.
Approximately 50% of youth with bipolar disorder
receive no treatment. Among those who do receive
treatment, approximately 50% do not receive bipolarspecific treatment, raising concerns about exposure
to antidepressants and/or stimulants in the absence
of mood-stabilizing medication.
Psychiatric and medical comorbidities are common,
present diagnostic and treatment challenges, and
vary depending on age and gender.
Adherence with established diagnostic criteria, including the requirements regarding sufficient number of
symptoms and the presence of episodes, may serve
to optimize diagnostic accuracy; automatic doublecounting of overlapping symptoms is not advised.
Children of parents with bipolar disorder are at
increased risk for several psychiatric diagnoses, but
especially bipolar disorder. Clinical risk factors for
pediatric bipolar disorder include major depressive
disorder, anxiety disorders, and disruptive behavior
disorders.

Acknowledgements
Dr. Goldstein is supported by the Canadian Institutes of Health Research, the
Depressive and Bipolar Disorder Alternative Treatment Foundation, the Heart
and Stroke Foundation of Ontario, the Ministry of Health and Long-Term Care
of Ontario, an investigator-initiated grant from Pfizer, and by donations to the
Sunnybrook Foundation.
Dr. Birmaher is supported by the National Institute of Mental Health (MH59929,
MH60952), and by an Endowed Chair in Early-onset Bipolar Disease.

12

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