IACAPAP Textbook of Child and Adolescent Mental Health

MOOD DISORDERS

Chapter

E.2

BIPOLAR DISORDERS
IN CHILDREN AND ADOLESCENTS
2019 edition
Rasim Somer Diler & Boris Birmaher

Rasim Somer Diler MD
Associate Professor of
Psychiatry & Medical Director,
Inpatient Child and Adolescent
Bipolar Services, Western
Psychiatric Hospital, Universityof Pittsburgh Medical Center,
Pitssburgh PA, USA
Conflict of interest: researchfunding from National Instituteof Health

Boris Birmaher MD
Director, Child & AdolescentAnxiety Program & Codirector,
Child and Adolescent Bipolar
Services, Western Psychiatric
Hospital, UPMC. Endowed
Chair in Early Onset Bipolar
Disease & Professor of
Psychiatry, University ofPittsburgh School of Medicine,
Pittsburgh PA, USA
Starry Night, Vincent van Gogh, 1889.
Museum of Modern Art, New York City

Conflict of interest: none
disclosedThis publication is intended for professionals training or practicing in mental health and not for the general public. The opinions
expressed are those of the authors and do not necessarily represent the views of the editors or IACAPAP. This publication seeks todescribe the best treatments and practices based on the scientific evidence available at the time of writing as evaluated by the authorsand may change as a result of new research. Readers need to apply this knowledge to patients in accordance with the guidelines andlaws of their country of practice. Some medications may not be available in some countries and readers should consult the specific drug
information since not all dosages and unwanted effects are mentioned. Organizations, publications and websites are cited or linked toillustrate issues or as a source of further information. This does not mean that authors, the editors or IACAPAP endorse their content
or recommendations, which should be critically assessed by the reader. Websites may also change or cease to exist.
©IACAPAP 2019. This is an open-access publication under the Creative Commons Attribution Non-commercial License. Use,
distribution and reproduction in any medium are allowed without prior permission provided the original work is properly cited andthe use is non-commercial.
Suggested citation: Diler RS, Birmaher B. Bipolar disorders in children and adolescents. In Rey JM & Martin A (eds), JM Rey’s
IACAPAP e-Textbook of Child and Adolescent Mental Health. Geneva: International Association for Child and Adolescent Psychiatryand Allied Professions 2019.

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IACAPAP Textbook of Child and Adolescent Mental HealthIt is now widely accepted that bipolar disorder (BD) occurs in children andadolescents and the controversy has shifted from a debate about whether it
can be diagnosed in youth to how it is diagnosed, how it can be distinguishedfrom other more common childhood psychiatric disorders, and how it
can be treated and prevented (Diler, 2007; Goldstein et al, 2017). BD severely
affects the normal development and psychosocial functioning of the child and isassociated with increased risk for suicide, psychosis and substance abuse, as well as
for behavioral, academic, social, and legal problems (Diler et al, 2019).

Despite concerns about
over-diagnosing BD, thisdisorder is still undiagnosed
in many children.

BD-I is classified under mood disorders and characterized in its classic
form by cyclic changes between mania and major depressive episodes. Other
subtypes of BD include episodes of major depression with hypomania (BD-II),
multiple episodes of hypomania with depressed mood but without clear episodesof major depression (cyclothymia), and subthreshold (i.e., shorter) episodes ofmania or hypomania with or without depression (other specified bipolar andrelated disorders, BD-OS). There are subtle diagnostic differences between theInternational Classification for Diseases-11 (ICD-11) and the Diagnostic andStatistical Manual of Mental Disorders, fifth edition (DSM-5), but in parallelwith the majority of reports in youth, unless otherwise specified, the DSM criteria
will be used in this chapter (APA, 2000; 2013). For the purposes of this chapter
the word “youth” denotes children and adolescents. The aim of this chapter is toreview the diagnosis and subtypes, epidemiology, age of onset and course, etiology
and risk factors, clinical presentation, differential diagnosis, and treatment of BD
in children and adolescents.

DIAGNOSIS AND SUBTYPES
It is important to use a common language between professionals (and withpatients and families) when describing, reporting, and monitoring mood changes
in youth. DSM-5 defines several subtypes of BD:•

Bipolar-I (BD-I)•

Bipolar-II (BD-II)•

Cyclothymic disorder•

Otherwise specified/unspecified bipolar and related disorder (BD-OS)•

Medication/substance induced BD, and•BD due to another medical condition.

Except for cyclothymia, the diagnostic criteria are the same for adults andchildren (APA, 2013). DSM-5 introduced some changes to BD, classified under
the heading of “bipolar and related disorders” (APA, 2013):•

In order to enhance the accuracy and facilitate earlier detection inclinical settings, the primary criteria for manic and hypomanic episodes
now include an emphasis on the presence of changes in activity andenergy, not just mood. In other words, in DSM-5, a manic episodediagnosis cannot be made without a change in activity or energy level,in addition to elated/irritable mood.

•

The “mixed episode” diagnosis of DSM-IV was eliminated and a new
specifier (“with mixed features”) has been added that can be applied toepisodes of mania or hypomania when depressive features (e.g., three

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IACAPAP Textbook of Child and Adolescent Mental Healthor more depressive symptoms) are present. It can also be applied toepisodes of depression when features of mania/hypomania are alsopresent. In contrast, ICD-11 keeps the “mixed episode” diagnosis
and defines it as “either a mixture or very rapid alternation between
prominent manic and depressive symptoms on most days during a periodof at least 2 weeks” (WHO, 2018).
•

A new specifier for “anxious distress” is now defined in DSM-5 to
identify patients with anxiety symptoms during the mood episodethat are not part of the bipolar and other anxiety disorders diagnostic
criteria.

•

Instead of the “BD-not otherwise specified” (BD-NOS) diagnosis
in DSM-IV, “other specified” and “unspecified” bipolar and relateddisorders categories were introduced in DSM-5 for patients that present
with mania/hypomania but who do not meet full BD-I or BD-II criteria.
“Other specified” is used when the reason for not meeting the full BD-I/
II criteria can be explained (e.g., not meeting the duration criteria—lessthan 7 days), and “unspecified” is used when no explanation is provided(e.g., in the emergency room setting when limited information can begathered). Similar to DSM-5, ICD-11 included “other specified andunspecified” bipolar or related disorder categories (WHO, 2018).

BD in young people
is an episodic illness
with subsyndromal andsyndromal episodes mainlywith depressive and mixed
symptoms and rapid moodchanges.

Bipolar Disorder I•

BD-I requires the presence or history of an episode of mania with orwithout a major depressive episode.

•To make a BD-I diagnosis both, symptom criteria—elation plus 3, or
irritability plus 4 manic symptoms, one of which should be increased
activity/energy level—and duration criteria, should be met in addition
to “significant functional impairment or psychosis” during mania. To
meet the duration criteria, mania should last at least 7 consecutive daysor require an inpatient admission anytime during the episode.

•In DSM-5, a manic episode is described as a distinct period ofabnormally and persistently elevated, expansive, or irritable mood andabnormally and persistently increased activity or energy level lasting atleast 7 consecutive days and present most of the day, nearly every day.
Other symptoms of mania are:

Click on the picture to accessthe transcripts of an interview
with David Axelson MD about
issues related to the rate of
BD diagnosis in youth.

–– Inflated self-esteem or grandiosity–– Decreased need for sleep (e.g., feels rested after only 3 hours of
sleep)–– More talkative than usual or pressure to keep talking–– Flight of ideas or subjective experience that thoughts are racing–– Distractibility (e.g., attention too easily drawn to unimportant or
irrelevant external stimuli), as reported or observed–– Increase in goal-directed activity (either socially, at work or school,or sexually) or psychomotor agitation–– Excessive involvement in activities that have a high potential for

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IACAPAP Textbook of Child and Adolescent Mental Health

Figure E.2.1

Mood episodes in bipolar disorder-I and bipolar disorder-II

BD: bipolar disorder

painful consequences (e.g., engaging in unrestrained buying sprees,sexual indiscretions, or foolish business investments).
•

In ICD-11, a manic episode is described as an extreme mood state
lasting at least one week unless shortened by a treatment intervention,
characterized by euphoria, irritability, or expansiveness, and by increased
activity or a subjective experience of increased energy, accompanied byother characteristic symptoms such as rapid or pressured speech, flightof ideas, increased self-esteem or grandiosity, decreased need for sleep,
distractibility, impulsive or reckless behavior, and rapid changes among
different mood states (i.e., mood lability) (WHO, 2018).

Bipolar Disorder II•

BD-II is characterized in DSM-5 by at least one major depressive episodeand at least one hypomanic episode (hypomania should last at least 4
consecutive days).

•

In ICD-11, the 4-day duration criterium is not specified; instead, ahypomanic episode is described as a persistent mood state characterized
by euphoria, irritability, or expansiveness, and excessive psychomotor
activation or increased energy, accompanied by other characteristic
symptoms such as grandiosity, decreased need for sleep, pressured
speech, flight of ideas, distractibility, and impulsive or reckless behavior
lasting several days (WHO, 2018).

•

Both DSM-5 and ICD-11 agree that hypomanic symptoms represent achange from the individual’s typical behavior but are not severe enoughto cause marked impairment in functioning.

Hypomania
Hypomania is a milder
form of a manic episode.
The patient should havedistinct change frombaseline functioning but
not have marked functional
impairment. Sometimes
patients actually like being
hypomanic because they
are able to do more things
such as working on more
projects.

Cyclothymic Disorder
Is characterized by numerous hypomanic episodes together with numerous
periods of depressive mood or loss of interest or pleasure that do not meet all thecriteria for BD or for a major depressive episode lasting at least one year—versus
2 years in adults (Van Meter et al, 2013).

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Click here to view a summaryof DSM diagnoses of BD
based on the type of moodepisode.

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IACAPAP Textbook of Child and Adolescent Mental Health

Bipolar Disorder Otherwise Specified (BD-OS)
BD-OS is used when there are features of hypomanic or mixed episodes that
do not meet diagnostic criteria for any of the more specific BD subtypes. Because
criteria for BD-OS are vague, researchers have developed clearer definitions to
identify other specified BD diagnosis, for example, at least 2-day long history of
hypomania or at least 4 shorter (≥ 4 hours each) episodes of hypomania (one less
symptom to meet the symptom criteria) (Axelson et al, 2011b).

BD-OS in youth is not amild or “soft” BD phenotype
with less impairment but
may developmentally exist
on a continuum with BD-I
(Axelson et al, 2011b).

EPIDEMIOLOGY
The prevalence of BD-I and BD spectrum disorders in adults is around
1-2% and 3-6%, respectively, and the majority of them had the onset before theage of 20 years (Carlson & Pataki, 2016; Perlis et al, 2009). In clinical populations
the prevalence of BD in youth in the US has been reported between 0.6% and 15%
depending on the setting, the referral source, and the methodology to ascertain
BD. Some studies, especially those in the US, have shown dramatic increases inrecognition and rates of BD in youth over the past 20 years and some authors haveraised the possibility of over diagnosis, whereas others highlight the possibility ofneglecting the existence of this condition in childhood (Diler et al, 2019).
A meta-analysis about epidemiology of BD in youth around the world
reported that the overall rate was 1.8% (95% CI, 1.1%–3.0%). The study, which
included 16,222 youth between the ages of 7 and 21 years from 1985 to 2007
(Van Meter et al, 2011), suggests that:•

Prevalence of BD-I in youth is consistent with the current prevalence
estimates of BD in adults•

The prevalence of BD-I in youth was not different in the US relative toother countries (e.g., the Netherlands, UK, Spain, Mexico, Ireland, and
New Zealand), and•Despite BD being diagnosed more commonly in clinical settings, theprevalence of BD in youth in the community is not increasing (Van
Meter et al, 2011).

Studies suggest that it
takes on average 10
years to identify and begin
treatment of BD, indicating
the need for timely
detection and treatment of
this serious illness.

Gender and Age Differences in Prevalence
Similar to adults, studies in clinical populations suggest that rates of bipolar
spectrum disorders in youth are equally common in males and females (Axelson
et al, 2006; Diler et al, 2019). However, BD-II and adolescent-onset BD are
more prevalent in females (Birmaher et al, 2009b). A large epidemiological study
in the US reported slightly higher rates of BD-I and -II in female than in maleadolescents (3.3% versus 2.6%, respectively) with increasing rates of BD witholder ages (Merikangas et al, 2010). The meta-analysis of international BD studies
concluded that BD can have its onset in childhood, but prevalence was muchhigher during adolescence (Van Meter et al, 2011).

Burden of Illness
The WHO indicates that BD is the 6th leading cause of disability in theworld. BD in youth is increasingly recognized as a significant public health

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There was no significant
difference in the mean ratesof BD in youth between US
and non-US studies, but US
studies had a wider rangeof rates, especially whena broader definition of BD
was used (Van Meter et al,2011).

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IACAPAP Textbook of Child and Adolescent Mental Healthproblem often associated with impaired family and peer relationships, poor
academic performance, high rates of chronic mood symptoms, psychosis,
disruptive behavior disorders, anxiety disorders, substance use disorders, medical
problems (e.g., obesity, thyroid problems, diabetes), hospitalizations, and suicide
attempts and completions (Diler, 2007; Diler et al, 2019). Moreover, youth withBD have higher behavioral health costs and greater utilization of medical services
compared with youth with unipolar depression or non-mood disorders. Patientswith undiagnosed BD may also have higher behavioral health costs than those withdiagnosed BD. Given the high rates of morbidity and mortality and the chronic
course of the condition, early diagnosis and treatment is critical (Birmaher &Axelson, 2005; Carlson & Pataki, 2016; Diler, 2007).

Early identification of BD inyouth is the key not only formood stabilization but also
to enable the child to follow
a normative developmental
path and prevent an
unrecoverable loss inthe child’s psychosocial
development and education(Birmaher & Axelson,2005).

AGE OF ONSET AND COURSERetrospective studies in adults with BD have reported that 10%–20% had
the onset before 10 years of age and up to 60% before the age of 20 (Diler, 2007;
Kozloff et al, 2010; Perlis et al, 2009). BD in adults is frequently preceded bychildhood disruptive behavior disorders and anxiety disorder. Early onset BD is
associated with a more severe course of the illness and poor outcome. Children
with pre-pubertal-onset of BD are reported as approximately 2 times less likely
to recover than those with post-pubertal-onset. In addition, individuals with prepubertal-onset had more chronic symptoms, spent more follow-up time with
subsyndromal mood symptoms, and had more polarity changes per year thanthose with post-pubertal-onset (Birmaher et al, 2009a; 2014; Carlson & Pataki,
2016; Diler, 2007; Holtzman et al, 2015).
Youth with BD show a continuum of symptom severity from subsyndromal
to full syndromal with frequent mood fluctuations. Earlier studies in youth
suggested high rates of chronicity of manic presentations, such as a 14% recovery
after 6 months (Geller et al, 2000), and high rates of rapid cycling (50%) withalmost no inter-episode recovery (Findling et al, 2001).
Naturalistic and follow-up studies have reported that 70% to 100% ofyouth with BD will eventually recover (e.g., show no significant symptoms
for 2 months) from their index episode. However, up to 80% will experience
recurrences (e.g., one or more recurrences in 2-5 years) despite ongoing treatment.
In addition, analogous to findings for adults, the prospective course in theseyouths is characterized by mood fluctuations of varying intensities throughout
60% to 80% of the follow-up time, particularly depressive and mixed symptoms,
and have frequent shifts in symptom polarity. During adolescence, there is a drastic
increment in the rates of suicidal ideation and attempts and substance abuse. In
addition, youth with BD show high rates of legal, social, familial, and academic
problems (Birmaher et al, 2009a; 2014; Diler, 2007; Diler et al, 2019). A recent
study evaluated more individualized course during a 9-year period identified four
longitudinal mood trajectories:•“Predominantly euthymic” course (24%)•“Moderately euthymic” course (35%)•“Ill with improving course” (19%), and•“Predominantly ill” course (22%) (Birmaher et al, 2014).

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Click on the image to watch
Dr. Birmaher talk about“What Happens Over Timewith Youth Who Have Been
Diagnosed With Bipolar
Spectrum Disorders” (36:06)

Early age of onset, long
duration, low socioeconomic
status, mixed or rapid
cycling episodes, psychosis,
subsyndromal mood
symptoms, comorbid
disorders, exposure tonegative life events, highexpressed-emotion, andfamily psychopathology
are associated with worse
course and outcome(Birmaher et al, 2009a; Diler,
2007).

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IACAPAP Textbook of Child and Adolescent Mental HealthWithin each group, on average youths were euthymic 84%, 47%, 43%,
and 12% of the follow-up time respectively. Better course was associated witholder age at onset of mood symptoms, less lifetime family history of BD andsubstance abuse, and less history at baseline of severe depression, manic symptoms,
suicidality, subsyndromal mood episodes, and sexual abuse (Birmaher et al, 2014).
Interestingly, the fact that a subgroup of BD youths has a mainly euthymic course
questions whether these subgroup needs lifetime treatment.
Individuals with BD and attention-deficit hyperactivity disorder showedfunctional recovery in 4 years in only 20% of cases (Biederman et al, 2004).
However, it is now agreed that BD in youth is not characterized by ultra-rapid
cycling or chronic mania but manifested by recurrent mood episodes—albeit more
frequent than in adults with BD (Birmaher et al, 2009a).

ETIOLOGY AND RISK FACTORSThe single best predictor of BD in youth is family history. Twin and family
studies have demonstrated that BD is a highly inherited illness with concordance
between identical twins of about 70%; that is, 2-3 times that for non-identicaltwins. Current studies indicate that multiple genes are likely to be responsiblefor BD but so far, they have not been identified. Interested profesionals may read
Schulze’s review (Schulze, 2010) or click here for a list of potential susceptibility
genes (Ikeda et al, 2018).
Subthreshold manic or hypomanic episodes were a risk factor for thedevelopment of manic, mixed, or hypomanic episodes in the offspring of parents
with BD (Axelson et al, 2015). Further longitudinal prospective analyses suggestthat offspring of BD parents with mood lability, depression/anxiety, subsyndromal
manic symptoms, and early-onset parental BD were at 50% risk to develop BD(Hafeman et al, 2016).
The above studies inform us about the risk factors for developing BD in
offspring of parents with BD for the group as a whole. However, they do nottell us about the risk of developing BD for an individual child. To do this, a risk
calculator has been developed recently (Hafeman et al, 2017b). If the calculator isexternally validated it may become a useful tool for clinical practice and research.
Despite BD being an inherited illness, there are other biological, social oremotional variables which can either precipitate BD or serve as protective factors
in people genetically predisposed (Bootsman et al, 2016; Diler et al, 2019; Pan etal, 2017). Research and clinical experience also suggest that trauma or stressful life
events can trigger an episode of BD; however, many episodes occur without anobvious or identifiable cause. In brief, the etiology is multifactorial with complex
interaction of biological vulnerabilities and environmental influences.

“One of the overall
goals of neuroimaging
is to understand what
differentiates children who
are at risk for BD from otherchildren. The ultimate goal
is to identify neurobiologicalmarkers (physical differencesin the chemistry andstructure of the brain) forBD so that we can more
effectively treat those whoare at risk for developing it”(DelBello, 2012). Click on
the picture below to watch
Dr Leibenluft’s talk about
how brain imaging data is
being combined with genetic
research to understand BD
and brain function (5:00)

Recent advances in neuroimaging, such as magnetic resonance imaging(MRI) and functional MRI (fMRI), indicate that neural circuits involved inemotion processing and regulation in BD youth are different from healthy peers(Diler et al, 2013; 2014; Hafeman et al, 2017a; Singh et al, 2012). The reduced
volume of the amygdala in adolescents with BD is one of the most consistentneuroimaging findings (Pfeifer et al, 2008). Neuroimaging findings in BD youth
need to be taken with caution because of small samples and other confounding

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IACAPAP Textbook of Child and Adolescent Mental Healthfactors such as subjects’ different mood phases (e.g., depressed, hypomanic,
euthymic) and the presence of comorbid disorders and medications.
BD youth display deficits in neurocognitive domains of attentional
set-shifting, visuospatial memory, working memory, cognitive flexibility, andexecutive functions (Dickstein et al, 2016; Doyle et al, 2005; Pavuluri et al,
2006b). Neurocognitive deficits also differentiated BD from unipolar depressed
youth (Murphy et al, 1999). Improvement of acute mood episode may accompany
improvement in neurocognitive functioning (e.g., verbal and working memory);
however, studies suggest that neurocognitive deficits may be independent of thechild’s mood state, can exist even when there are no signs of mania or depression,and may have long-term implications for reduced functional ability (Frias et al,
2017; Pavuluri et al, 2009).

COMORBIDITY
Comorbid disorders, particularly disruptive behavior disorders, attention
deficit hyperactivity disorder, and anxiety disorders are very common. Presence ofcomorbid conditions adversely affect the clinical course of BD (Sala et al, 2014;
Yen et al, 2016). The prevalence of comorbid disorders depends on the methods
utilized for ascertainment and the sample studied (e.g., more common in clinicalversus community, and in children versus adolescents—with more ADHD and
oppositional defiant disorder in the former and more conduct and substance use
disorders among the latter).

CLINICAL PRESENTATIONS
The practice parameters for BD of the American Academy of Child andAdolescent Psychiatry recommends that clinicians should adhere to the DSM,
including duration criteria (McClellan et al, 2007). There is consensus thatchildren and adolescents can fulfill DSM criteria for BD-I and II. However, in fact,
the majority of youth are diagnosed in the US with “other specified BD” because
they do not meet the duration requirements for BD-I or II (Axelson et al, 2011b).
Although the presentation of BD is heterogenous, the most common
symptoms across subtypes are increased energy, irritability, mood lability,
distractibility, and increased goal directed activity (all approximately in 75% ofcases); hallucinations and delusions are the least frequent (about 26% of cases)(Van Meter et al, 2016). Grandiosity and hypersexuality are the most specificsymptoms but are not as common (57% and 32%, respectively).

Presence of multiple
comorbid conditions is very
common in youth with BD
and they adversely affectthe course of the illness

Depression is usually
the first mood episodeobserved in many youth
with BD; however, adiagnosis of BD cannot
be made before a history
or presence of mania/
hypomania. Carefulassessment of current andpast symptoms of mania/
hypomania is necessary
for all youth, especially inthose who present withdepression.

It is very important to evaluate whether mood and symptoms are abnormal,
clearly different from the youth’s usual mood and behavior, above and beyond the
young person’s developmental level, the context where the symptoms occur, andthe extent to which the symptoms affect functioning.

Episodicity
Despite suggestions by some investigators that episodicity—distinct periodsof abnormal mood and accompanying symptoms—is not needed to diagnose
pediatric BD, most investigators, clinicians, and the AACAP guidelines recommendthat episodicity be required for diagnosis (Leibenluft et al, 2003; McClellan et

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IACAPAP Textbook of Child and Adolescent Mental Healthal, 2007). In fact, it is suggested to focus on determining the presence of moodepisodes first and then ascertain the extent to which manic/hypomanic symptoms
are present during an identifiable time frame.

Irritability“There now is substantial consensus that chronic irritability, regardless of
explosiveness or severity, is not sufficient for a diagnosis of BD, in contrast withformulations that focused on rages or severe aggression. However, irritability
is commonly present in youth with BD. Counting irritability as part of thediagnostic criteria for a manic or hypomanic episode requires that the irritability
either begins or significantly increases in intensity in conjunction with the presenceof accompanying manic symptoms.” (Goldstein et al, 2017).
It is important to remember that irritability is part of the diagnostic criteria
for many other disorders such as oppositional defiant, major depressive, generalized
anxiety, and post-traumatic stress disorders and is frequently present in youth
with other psychiatric diagnoses such as ADHD and pervasive developmental
disorders. Therefore, irritability has low specificity for BD; it can be considered as
an analogous to fever or pain in physical illness, which suggests that “somethingis wrong” (Kowatch et al, 2005). On the other hand, the absence of episodes of
irritability may decrease the likelihood of BD.
In contrast to episodic irritability, the chronic presence of this symptom has
been recently conceptualized as the core feature of a new condition: “disruptive
mood dysregulation disorder,” also know as temper dysregulation disorder withdysphoria and severe mood dysregulation (see Chapter E.3 of the e-Textbook) .

Chronic irritability was
associated with ADHD,
oppositional defiant
disorder, and major
depressive disorder rather
than BD. Episodic irritability
was associated withincreased risk to develop
BD and anxiety (Leibenluft
et al, 2006)

Click here to view anexpert panel discussion
including Gabrielle Carlson(US), Samuele Cortese(UK), Robert Findling(US), Benjamin Goldstein(Canada), Carmen Moreno(Spain), Andrea Cipriani(UK), and Michael Ostacher(US) about the diagnosis
and irritability in youth withBD (58:55)

Subthreshold Presentations
Subthreshold or subsyndromal presentations are those in which the young
person appears to show significant manic symptomatology but do not meetthe criteria for BP-I or BP-II disorders, for example the duration requirements.
Follow-up studies (e.g., Birmaher et al, 2009a; DelBello et al, 2007) have shownthat the most common presentation of BD is subsyndromal, particularly with
mixed and depressive symptomatology. For example, the COBY study showedthat during 60% of the 4-years of follow-up, children and adolescents with BD
experienced mood symptoms and 40% of the time were subsyndromal (Birmaher
et al, 2009a). Furthermore, subsyndromal symptoms were accompanied bysignificant psychosocial difficulties and increased the risk of suicidality, legal
problems, and substance abuse. In addition, about 50% of youth with the COBY
definition of “other specified BD” converted into BD-I or II later on, especially ifthey had family history of mania or hypomania (Axelson et al, 2011b). The abovefindings indicate the need for early recognition and treatment of subsyndromal
symptomatology. Based on the COBY study data allowed to build and validate
a risk calculator which predicted the 5-year risk of conversion from subthresholdmania to BD-I/II with 71% discrimination (Birmaher et al, 2018).

About 50% of the youth
with BD-NOS, particularly
those with a family historyof mania or hypomania,
converted into BD-I or II
during follow up (Axelson etal, 2011b).

Bipolar Depression
Similar to in adults, depressive episodes are the most common

manifestation of BD in children and adolescents—both in frequency and duration

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9IACAPAP Textbook of Child and Adolescent Mental Health(Birmaher et al, 2009a). The COBY study reported that during naturalistic followup most recurrences after the index episode were major depressive episodes (60%),
followed by hypomanic (21%), manic (15%), and mixed (5%) across all subtypes(Birmaher et al, 2009a). However, depression is commonly underdiagnosed.
Bipolar depression tends to be more severe, has more mixed manic symptoms andself-harm behaviors (Diler et al, 2017a), higher comorbidity with oppositional
defiant disorder, conduct disorder and anxiety disorders (Uchida et al, 2015), andincreased risk for psychosocial impairment and suicide than unipolar depression(Wozniak et al, 2004). Careful monitoring of developmental progression of mood
symptoms is critical because:•

Many adolescents experience depression first, before the emergence of
mania

•

The presence of subsyndromal manic symptoms during depression
significantly increases the risk for progression to a manic episode(Diler et al, 2017b), and•If the manic symptoms are ignored, the course of the illness is likely tobe recurrent with progressively more severe and refractory episodes ofboth mania and depression (Geller & Luby, 1997).

In comparison withadolescent-onset BD,
childhood-onset BD
manifest itself withmore subsyndromalpresentations, rapid moodchanges and not welldefined grandiose ideation.
Also, children with BD havea higher familial loading
for mood disorders anda different pattern ofcomorbid disorders thanadolescent-onset BD. In
contrast, adolescent-onset
BD is associated with more
severe and more “classic”(e.g., adult-like) mood
symptomatology (Birmaher
et al, 2009c).

Preschool and Preadolescence Presentations
It is reported that mood lability (e.g., rapid mood variation with several
mood states within a brief period of time, which appears internally driven without
regard to the circumstances) and irritability/anger, are more characteristic ofchildhood-onset rather than adolescent-onset mania. Adolescents with BD, relative
to children with BD, have more adult-like manic symptomatology (e.g., more
typical and severe manic and depressive symptomatology) (Birmaher et al, 2009c).
Given the emotional and cognitive developmental stage of preschool
children (aged from 3 to 7 years), questions have been raised regarding the validityof manic symptoms such as grandiosity and elation at this age. In parallel, the
AACAP guidelines suggest that clinicians should be cautious when making BD
diagnoses in children younger than 6 (McClellan et al, 2007). Few studies suggestthat preschool children may suffer from BD.

DIFFERENTIAL DIAGNOSISIt is important for clinicians to have a working knowledge of normative
cognitive, behavioral, and affective development and cultural norms so that they
can determine whether certain behavior is normative or pathological at the child’s
stage of development. It is difficult to diagnose BD in youth given the variability
in the clinical presentation, high comorbidity, overlap of symptoms with otherpsychiatric disorders, effects of development on symptom expression, children’sdifficulties in verbalizing their emotions, and the potential effects of medications.
Presence of past and current mania/hypomania should be a part of every childpsychiatric assessment (please see Tables 1 and 2). Clinicians must be cautious
about attributing symptoms to mania or hypomania unless they show a clear
temporal association with the abnormally elevated, expansive and/or irritable

Bipolar disorder

E.2

Clinicians should carefully
observe whether thesymptoms of the comorbid
disorder disappear or
persist while children
with BD are euthymic
and whether symptoms
associated with BD worsen
during the mood episode.

10

IACAPAP Textbook of Child and Adolescent Mental Healthmood. For example, substance use can complicate the clinical picture of BD, but
the essential feature of a drug-induced mood disorder is the onset of symptoms
in the context of drug use, intoxication, or withdrawal. Both substance use andBD can co-exist (e.g., dual diagnosis). However, mood symptoms that start before
or persist longer than a month after cessation of drug use can be considered as
the primary disorder (APA, 2013). Furthermore, chronic symptoms such as
hyperactivity or distractibility should not be considered evidence of mania unlessthey clearly intensify with the onset of abnormal mood. Prolonged presentations of
non-specific manic-like symptoms that do not change in overall intensity shouldraise the possibility of an alternative psychiatric diagnosis (Birmaher & Axelson,
2005; Diler et al, 2019).
The presence of psychotic symptoms calls for differential diagnoses withother psychiatric disorders such as schizophrenia. In that case onset is usuallyinsidious and the patient lacks the engaging quality of mania. The following
Table E.2.1
•
•
•
•
•
•

Bipolar disorder versus disruptive behavior disorder

If the behavior problems only occur while the child is in the midst of an episode of mania or depression, and the behavior
problems disappear when the mood symptoms improve, the diagnoses of oppositional or conduct disorder should not be
made.
If a child has “off and on” oppositional or conduct symptoms or these symptoms only appear when the child has moodproblems, the diagnosis of BD (or other disorders such as recurrent unipolar depression or substance abuse) should beconsidered.
If the child had oppositional behaviors before the onset of the mood disorders, both diagnoses may be given.
If a child has severe behavior problems that are not responding to treatment, consider the possibility of a mood disorder(bipolar and non-bipolar depressions), other psychiatric disorder (e.g., ADHD, substance abuse), and/or exposure to
stressors.
If a child has behavior problems and a family history of bipolar, consider the possibility that the child has a mood disorder(unipolar major depression or BD disorder).
If a child has behavior problems and is having hallucinations and delusions consider the possibility of BD disorder. Also
consider the possibility of schizophrenia, use of illicit drugs/alcohol, or medical/neurological conditions.

Birmaher B. New Hope for Children and Adolescents with Bipolar Disorders. New York: ©Three Rivers Press, 2004, reproduced withpermission.

Table E.2.2

Bipolar disorder versus attention deficit hyperactive disorder (ADHD)

Suspect the presence of bipolar disorder in a child with ADHD if:•
The “ADHD” symptoms appeared later in life (e.g., at age 10 years old or older)•
The symptoms of “ADHD” appeared abruptly in an otherwise healthy child•
The ADHD symptoms were responding to stimulants and now are not•
The “ADHD” symptoms come and go and tend to occur with mood changes•
A child with ADHD:− Begins to have periods of exaggerated elation, grandiosity, depression, no need for sleep, inappropriate sexual
behaviors− Has recurrent severe mood swings, temper outbursts, or rages− Has hallucinations and/or delusions− Has a strong family history of BD in his or her family, particularly if the child is not responding to appropriate
ADHD treatments.
Birmaher B. New Hope for Children and Adolescents with Bipolar Disorders. New York: ©Three Rivers Press, 2004, reproduced withpermission.

Bipolar disorder

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11

IACAPAP Textbook of Child and Adolescent Mental Healthcharacteristics would favor a BD diagnosis: good affective contact, transient rather
than persistent speech incoherence and poverty of content, good response to moodstabilizers, and family history of BD. However, the first episode of mania canpresent with severe thought disorder and hallucinations making the differential
diagnosis between schizophrenia and BD difficult. In these cases a careful andongoing follow-up helps to clarify the diagnosis (Diler, 2007; Diler et al, 2019).

ASSESSMENT
Psychiatric Interviews
It is necessary to evaluate the frequency, intensity, number, and duration(FIND) when assessing mood episodes. The most widely used interviews in BD
studies are the Kiddie Schedule for Affective Disorders and Schizophrenia for School
Age Children—Present and Lifetime version (K-SADS-PL) (available for free athttps://www.pediatricbipolar.pitt.edu/resources/instruments) and the Washington
University KSADS (WASH-U-KSADS). However, these interviews are lengthy
and time-consuming, are mainly used for research purposes, and require trainingof the interviewer. Thus, symptom checklists for BD and depressive disorders
based on the DSM criteria are also useful (please see the “Child and Adolescent
Bipolar Spectrum Assessment Report” in the appendix).

Clinician-Based Rating Scales
Two clinician-based rating scales are currently used for the assessmentof manic symptoms and their severity in youth, the Young Mania Rating Scale(YMRS;) (Young et al, 1978) and the KSADS Mania Rating Scale (KSADS-MRS)(available online at the above link for the K-SADS). A recent study found that the
YMRS is not a valid measure for BD in youth (Youngstrom et al, 2015).

Youth, Parent, and Teacher Rating Scales
Parental reports appear to be more accurate in identifying mania than youth
or teacher reports (Youngstrom et al, 2015). The General Behavior Inventory (GBI)(Youngstrom et al, 2008), the parent version of the YMRS (P-YMRS), the parent
version of the Mood Disorder Questionnaire (MDQ) (Wagner et al, 2006a), andmore recently the Child Mania Rating Scale, Parent Version (CMRS-P) (Pavuluri etal, 2006a) have been shown to have appropriate psychometric properties and canbe useful to screen for BD symptoms in youth.
The Parent MDQ has the lowest reading level and most translations into
other languages but is no longer in the public domain (the self-rating version foradolescents is available here. The parent GBI-10 has the most research data, issensitive to treatment effects, but has the highest reading level (it may be available
from the author Eric Youngstrom. It has been suggested that the parent CMRS -10(Henry et al, 2008) is the most specific instrument for screening of BD in youth
and has a teacher version. A list of instruments and scales used in BD in youth canbe found here.
Other parent-reported instruments have been used to screen dimensional
psychopathology in youth such as the Child Behavior Checklist (CBCL), but these
instruments are not specific or useful for ruling in mania (Diler et al, 2009). On

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12

IACAPAP Textbook of Child and Adolescent Mental Healththe other hand, the CBCL or its subscales (e.g., sum of its aggression, attention,
and anxiety/depression subscales—CBCL-dysregulation profile, formerly
proposed as the “bipolar profile”) may reflect symptom severity, comorbidity, orfunctional impairment and low scores may be helpful in ruling out mania (or any
psychopathology) (Diler et al, 2007; Youngstrom et al, 2005b).

Mood Timelines or Diaries
These instruments, which use school years, birthdays, and holidays as
anchors, can help children, parents and clinicians to visualy represent the courseof their mood, identify events that may have triggered symptoms, and to examine
the relationship between treatment and response. Many of these instruments use
colors or ratings from 0-10 to chart daily changes in mood along with significant
stressors, illnesses, and treatments. We include in the appendix an example ofthese tools (the Mood & Energy Thermometer) developed at the inpatient childand adolescent bipolar services at the University of Pittsburgh. Readers can also
click here to access other instruments for mood charting. Mobile devices are also
increasingly used to monitor youth’s self-report sleep and mood changes.

Mood time lines (moodmonitoring) instruments
should be user (child)friendly and can be
modified (according to
the child’s age, culture
and interests) to increase
compliance.

Other Areas
Psychosocial Functioning
It is imperative to obtain information from multiple informants to accurately
assess changes in functioning, which should be measured against what would be
the expected level of functioning for a child given their culture, age and intellectual
capabilities.
Level of Care
Clinicians should also evaluate the appropriate intensity and setting of care(e.g., outpatient versus inpatient or partial hospitalization). The level of care will
depend on factors such as the severity of mood symptoms, the presence of suicidal,
homicidal symptoms, and risk for lethality, psychosis, substance dependence,agitation, child’s (and parents’) adherence to treatment, parental psychopathology,
and family environment.
Medical Conditions
The presence of medical conditions that may trigger or worsen mood
symptoms should be assessed. No biological or imaging tests exist for the diagnosisof BD. However, thyroid functioning (e.g., TSH) and whole blood count, B12,
folate, iron levels can be obtained when a first mood episode of BD is identified(see below additional lab tests that may be necessary before or during medication
treatment). A more detailed organic work-up may be required if a first episodepsychosis is considered in differential diagnosis (see Chapter H.5 of the e-Textbook).

TREATMENTThe treatment of BD has three stages: acute, continuation, and maintenance.
The goal of the acute phase is to control or ameliorate the acute symptoms that are
affecting the child’s psychosocial functioning and well-being or endangering the

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Team approach
Psychiatrists,
psychologists, behavioral
and developmental
pediatricians, social
workers, school counselors
and teachers, and manyother professionals who are
involved in treating the childshould work together as ateam so optimal care canbe attained in the medical,
educational, family, andsocial domains. It is very
important to consider theparents, the child, and theschool as a part of thisteam and include them indecision making.

13

IACAPAP Textbook of Child and Adolescent Mental Healthchild’s life. Continuation treatment is required to consolidate the response during
the acute phase and avoid relapses. The main goal of the maintenance phase is to
avoid new episodes or recurrences. The choice of pharmacological, psychosocial,or combined (pharmacological and psychosocial) treatment for each of these stages
depends on the severity, phase of illness, subtype of BD, chronicity, comorbid
disorders, child’s age, family and patient preference and expectations, availabilityof experts in psychotherapy, family and environmental circumstances, and family
psychopathology.

A balanced daily schedulemaintained throughpractical lifestyle habits,
such as regular sleep
patterns and consistentdaily routines may improve
BD symptoms whileirregular sleep patterns may
induce mood episodes.

PSYCHOEDUCATION
Psychoeducation and support start in the assessment phase and are
indicated in every phase of treatment. Family members and the patient should
be informed about the causes, symptoms, course, and different treatments, andthe risks associated with each treatment option as opposed to no treatment. The
patient and family should be prepared for what is likely to be a recurrent and often
chronic illness with frequent fluctuations in the child’s mood, and the importanceof good adherence to treatment. This will require a good deal of time. In addition,
restoration of hope and reversal of demoralization for the child and parents andcase management (e.g., negotiation with school and parents about reasonable
expectations) may be necessary (Birmaher & Axelson, 2005; Diler et al, 2019).
Sleep hygiene and routine are important, especially because sleep deprivation
leads to worsening of symptoms (please see Table E.2.3), thus ensuring a stable
circadian rhythm is important.

To assist withpsychoeducation, dedicatedassociations and several
other websites and books
are available including:Depression and Bipolar
Support Alliance (DBSA)
Guide for BD, and against
stigma.

Acute Treatment
The current evidence is derived from open-label, retrospective analyses, casereports, and RCTs that are summarized in more detail in McClellan et al (2007),and (Liu et al, 2011). There are very few studies targeting prepubertal children(Geller et al, 2012), bipolar depression, and the treatment of bipolar depression in
the context of comorbid disorders such as anxiety and ADHD.
In order to avoid unnecessarily high dosages and increasing the risk of side
effects and poor adherence to treatment, unless the child is too agitated, acutely
suicidal, and/or psychotic, it is recommended to start with a low dose and increase
dosage slowly, according to response and side effects. In general, and until further
studies suggest otherwise, dose of anticonvulsants and SGAs, as well as target bloodlevels of lithium and some of the anticonvulsants, are similar to those in adults
with BD. However, it is possible that children and adolescents may need higher
lithium blood concentrations, close to 1 mEq/dl (Geller et al, 2012), because it
seems that, relative to adults, children and adolescents have lower ratios of brainto-serum lithium concentration (Birmaher & Axelson, 2005).

PHARMACOTHERAPY
Acute Manic/Mixed Episodes
The effectiveness of monotherapy with lithium, valproate, carbamazepine
and second generation antipsychotics (risperidone, aripiprazole, quetiapine,olanzapine, asenapine, ziprasidone, and cariprazine) are broadly comparable in

Bipolar disorder

E.2

When planning treatment
in each phase, it is very
important to take into
account quality of life issues
for youth with BD that would
consider:•Cultural differencesand expectations•
Meaningful
relationships withfamily, peers, mentors,
coaches, and teachers•
Optimal academic
performance•
Optimal occupational
performance as it
pertains to endeavors
such as music, art,
dance, athletics•
Other personallyrewarding areasfrom which the youth
derives a sense ofcompetency, mastery,and pleasure.

14

IACAPAP Textbook of Child and Adolescent Mental Health

Table E.2.3
Sleep hygiene. Tips from the American Sleep
Association.
Maintain a regular sleep routine•
Go to bed at the same time. Wake up at the same time. Ideally, your schedule
will remain the same (+/- 20 minutes) every night of the week.
Avoid naps if possible•
Naps decrease the “sleep debt” that is so necessary for easy sleep onset.
•
Each of us needs a certain amount of sleep per 24-hour period. We need thatamount, and we don’t need more than that.
•
When we take naps, it decreases the amount of sleep that we need the nextnight – which may cause sleep fragmentation and difficulty initiating sleep, andmay lead to insomnia.
Don’t stay in bed awake for more than 5-10 minutes.
•
If you find your mind racing, or worrying about not being able to sleep during
the middle of the night, get out of bed, and sit in a chair in the dark. Do yourmind racing in the chair until you are sleepy, then return to bed. No TV orinternet during these periods! That will just stimulate you more than desired.
•If this happens several times during the night, that is OK. Just maintain yourregular wake time, and try to avoid naps.
Don’t watch TV or read in bed.
•
When you watch TV or read in bed, you associate the bed with wakefulness.
•
The bed is reserved for two things – sleep and hanky panky.
Do not drink caffeine•
The effects of caffeine may last for several hours after ingestion. Caffeine canfragment sleep, and cause difficulty initiating sleep. If you drink caffeine, use it
only before noon.
•
Remember that soda and tea contain caffeine as well.
Avoid inappropriate substances that interfere with sleep•
Cigarettes, alcohol, and over-the-counter medications may cause fragmented
sleep.
Exercise regularly•
Exercise before 2 pm every day. Exercise promotes continuous sleep.
•
Avoid rigorous exercise before bedtime. Rigorous exercise circulates
endorphins into the body which may cause difficulty initiating sleep.
Have a quiet, comfortable bedroom•
Set your bedroom thermostat at a comfortable temperature. Generally, a little
cooler is better than a little warmer.
•
Turn off the TV and other extraneous noise that may disrupt sleep. Background“white noise” like a fan is OK.
•
If your pets awaken you, keep them outside the bedroom.
•
Your bedroom should be dark. Turn off bright lights.
If you are a “clock watcher” at night, hide the clock.
Have a comfortable pre-bedtime routine•
A warm bath, shower•
Meditation, or quiet time

Bipolar disorder

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15

IACAPAP Textbook of Child and Adolescent Mental Healthnon-psychotic manic/mixed episodes (Findling & Ginsberg, 2014; Liu et al, 2011),
although less so than in adults (Goldstein et al, 2017). Recent studies suggest that
SGAs may be more efficacious than the traditional mood stabilizers (i.e, lithium
and anticonvulsants) but it should be kept in mind that youth are extra‐sensitive
to the metabolic side effects of SGAs (Liu et al, 2011).

Interested readers may visit
the US clinical trials website
and search for ongoingstudies of BD in youth.

Partial Responders and Non-Responders
In patients who do not respond to the initial monotherapy or who do nottolerate the medication, clinicians can try to:••••

Stop mood destabilizing medication (e.g., antidepressants)
Optimize the current treatment
Switch to a different mood stabilizer, or
Combine the monotherapy with other treatment options.

While it is ideal to use the lowest dose of medication possible to minimizeside effects, some patients may require higher amounts. In addition, someresearchers recommend short-term adjuvant medications during the acutephase of monotherapy. For example, lorazepam and clonazepam sometimes aretemporarily used for the management of acute agitation or insomnia (Birmaher& Axelson, 2005), monitoring the possibility of behavioral disinhibition causedby these medications. Despite limited research supporting its efficacy, some youth
with BD may benefit from melatonin. For combined medication treatment, it issuggested that using two mood stabilizers with different mechanism of action—such as lithium or an anticonvulsant—with a SGA may be more effective thanmonotherapy (Liu et al, 2011).

Hypomania
There are no studies in children and adolescents that specifically address thetreatment of hypomania. Until research becomes available, for those youth whose
hypomanic symptoms significantly impair their function, similar treatments to
those described for mania are recommended.

Bipolar Depression
Youth with bipolar depression spend substantial amounts of time burdened
by depressive symptoms or major depression that significantly impair their
psychosocial functioning and increase the risk for suicide. However, there are few
studies in youth with bipolar depression. The FDA has approved the combinationof olanzapine and fluoxetine for bipolar depression in youth aged 10‐17 years. In a
RCT of monotherapy with lurasidone, depressive symptoms significantly decreased
in children and adolescents with bipolar depression. Long-term treatment withlurasidone 20 mg/day was found effective in reducing depressive symptoms over
one year and the FDA has approved lurasidone for 10-17 year-olds (DelBelloet al, 2017). In contrast to findings in adults, a RCT reported that quetiapine
XR was not superior to placebo in youth with BD-I/II (Findling et al, 2014b).
In the absence of more research data for young people, treatment strategies canbe extrapolated from evidence obtained in adults. This includes using lithium,
lamotrigine, valproate, cariprazine, or a combination of anticonvulsant or an SGA

Bipolar disorder

E.2

If a child does not respondto treatment at any stage,factors associated with
non-response need to beconsidered, such as:•
Misdiagnosis•
Poor adherence totreatment•
Presence of comorbid
psychiatric andmedical conditions,and•Ongoing exposure
to negative events(family conflict, abuse,etc.).

16

IACAPAP Textbook of Child and Adolescent Mental Healthwith an antidepressant (Earley et al, 2019; Nivoli et al, 2011).
An open-label study with omega-3 fatty acids showed minimum to modest
improvement in depression symptoms in bipolar youth with good tolerance(Wozniak et al, 2007). Light therapy may be considered for subjects with recurrent
seasonal depression. Transcranial Magnetic Stimulation has also been suggested ina few small studies but needs to be further evaluated (Birmaher & Axelson, 2005;
Goldstein et al, 2017).
Electroconvulsive therapy (ECT) may be useful for severely impairedadolescents with manic or depressive episodes of BD-I if other treatments areeither not helpful or cannot be tolerated (McClellan et al, 2007).

Treatment of Comorbid Conditions
BD in youth usually presents with comorbid conditions that may worsen
the prognosis. It is recommended to use the most effective medications andpsychosocial treatments for each specific comorbid disorder and treatment for eachcomorbid disorder should begin sequentially. Sometimes medications for BD may
also be effective for the other psychiatric disorder (Birmaher & Axelson, 2005;
McClellan et al, 2007).
In general, before treating the comorbid disorder(s), it is recommended to
first stabilize the symptoms of BD, especially if the child’s comorbid symptoms(e.g., ADHD, behavior problems) appear to be secondary to the mood disorder(mania, depression, or both) (Birmaher & Axelson, 2005; Diler et al, 2019). If
the comorbid conditions cannot be attributed to BD or do not improve after
the symptoms of mania/hypomania subside, treatment for both the BD and thecomorbid conditions is indicated, especially if they have comorbid substance use. If
available, psychosocial treatments should be tried before adding new medications.
Amphetamine and methylphenidate preparations and atomoxetine
are treatment options for ADHD. For comorbid anxiety disorders, cognitivebehavioral therapy can be tried first. Because selective-serotonin reuptake inhibitors(SSRIs) are effective in treating anxiety disorders, for those with severe anxiety who
did not respond to therapy, SSRIs can be tried with caution in combination witha mood stabilizer.

Monitoring Pharmacotherapy and Clinical Concerns
Because all psychotropic drugs can cause important adverse effects, a carefulrisk-benefit analysis is needed (and should be discussed with the parents and youth)
when initiating pharmacologic treatment. Click here to access the US FDA website
to review updated information about the safety of psychotropic medications.
The list of prescription drugs that interact with psychotropic medications
is long and should be checked prior to prescribing any new medication. There
are several websites and smart phone applications (e.g., Micromedex Drug
Information by Thomson Reuters or Medscape) that provide updated information
on drug interactions.
A pregnancy test should be performed in all post-menarche females atbaseline and whenever sexual activity is a possibility during follow-up (manyof the medications for BD are teratogenic). Urine drug screen may be ordered

Bipolar disorder

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17

IACAPAP Textbook of Child and Adolescent Mental Healthin adolescents at baseline and then as necessary. Height and weight (e.g., bodymass index—BMI), vital signs, and waist circumference should be recorded ateach visit. Keep in mind that laboratory tests are not a replacement for clinicalevaluation (e.g., physical exam, family history of cardiac, diabetes, and thyroid
diseases) and it is important to review signs and symptoms of potential adverse
events with patients and their families as well as emphasize the need to contact
the prescribing physician if symptoms occur (e.g., rash with lamotrigine and otheranticonvulsants).
Tables E.2.4 and E.2.5 summarize common side effects from moodstabilizers and gives general monitoring guidelines based on recommendations
from FDA package inserts and typical practice from our BD clinic and research
center.

It is very important to pay aclose attention to patients’
own description of what
the important side effects
are and what the side
effects mean to them. For
example, a patient may
become noncompliant withlithium (without telling thedoctor), because of weight
gain, acne or tremor.

Lithium
The target serum level of lithium in acute treatment is 0.8 to 1.2mEq/L,
to be reduced to 0.6 to 0.8mEq/L once euthymia has been achieved. Lithium
has a narrow therapeutic widow (blood levels between 0.6 and 1.2 mEq/L) andsevere lithium toxicity can cause permanent renal and neurological damage oreven death. Dose should be titrated for each individual because tolerability varies
among patients and some individuals will be symptomatic at lower blood levels,
although initial symptoms of toxicity usually do not manifest until blood levels areabove 1.5 mEq/L.
Patient and parents should be informed about symptoms associated withlithium toxicity (e.g., dizziness, clumsiness, unsteady gait, slurred speech, coarse
tremors, abdominal pain, vomiting, sedation, confusion and blurry vision,
behaving like a drunk person). If a patient has difficulty taking fluids or having
excessive fluid loss (e.g. nausea, vomiting, diarrhea, febrile illness), lithium doseshould be reduced or temporarily held until regular fluid intake is resumed. If othersymptoms of lithium toxicity occur in addition to gastrointestinal distress, referral
for immediate evaluation is necessary (Birmaher & Axelson, 2005; Diler et al,2019). Blood levels should be obtained as early as 5-7 days after each dose increase,and immediately if clinical symptoms of toxicity occur. In addition, other baselinelaboratory tests such as those for thyroid and kidney functioning are necessary atbaseline and during follow up (please see Tables E.2.4 and E2.5). Patients should
be counseled to maintain adequate hydration during vigorous exercise or on hot
days, and avoid major changes in salt, caffeine or fluid intake. In addition, theymust notify physicians and pharmacists that they are taking lithium, and not
to take substances that interact with lithium. Common non-prescription drugs
and substances that can elevate lithium levels include most non-steroidal antiinflammatory drugs (acetaminophen does not), alcohol and marijuana. Caffeine
tends to lower lithium levels (Birmaher & Axelson, 2005).
Anticonvulsant Mood Stabilizers
These medications have neurological, cognitive, and gastrointestinal side
effects that can usually be managed by dose adjustments. Dose increases should
be gradual and periodic blood tests are suggested (see Table E.2.5) to monitor
the blood level of many of them and for rare but serious side effects (e.g., hepatic
failure, pancreatitis, thrombocytopenia). It is very important that patients and
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Click on the picture to visit
the US FDA website to view
updated information about
the safety of psychotropic
medications.

18

E.2

Weight gain
TremorNauseaDiarrhea
Cognitive
dulling
Sedation,fatigue
AtaxiaDizziness

•
•
•
•
•

•
•

•

•
•

•
•

Polyuria
Polydipsia
Tremor
Weight gain
NauseaDiarrhea
Hypothyroidism
Cognitive
dulling
Sedation,
Leukocytosis

•
•
•
•
•

Common

•
•

•

•
•

•

•
•
•

•

Serum
transaminase
elevation
Alopecia
Elevated
testosterone
Polycystic ovary
syndrome
Rash
Hair loss

New onset or
exacerbation ofacne or psoriasis
Bradycardia
Hair loss
ECG changes(T-waveflattening)

UncommonHepatic failure
Thrombocytopenia
Pancreatitis
Severe dermatologicalreactions
Myelosuppression
Anticonvulsant
hypersensitivity
syndrome

•
•
•
•
•
•

•
•
•
•
•
•

•
•
•

Kidney, brain damage
and death (due to acutetoxicity)
Decreased renal function
Pseudotumor cerebri
Extrapyramidal
symptoms
Movement abnormalities
Nystagmus
Seizures
Hyperparathyroidism
Sinus node dysfunction
Arrhythmias

•

Rare

•
•
•
•

•

•
•
•
•
•
•
•
•

CBC withdifferential &platelet count
AST, ALT
LipaseWeightMenstrual history

BUN
Creatinine
Urinalysis
TSH, Free T4
CBCElectrolytes
Calcium, Albumin
WeightBaseline tests

•
•
•

•

•

•
•
•
•
•
•
•

Divalproex
level
PlateletCount
AST, ALT
WeightMenstrual
history

Lithium level
BUN
Creatinine
Urinalysis
Calcium
Albumin
WeightFollow-up
tests

•

•

•

•

•

Each1 dosechange and
PRN
Every
2weeks x2,
then qevery monthx2, thenevery 3-6
monthsEach1 dosechange &every 3-6
months and
PRN
Every 3-6
monthsTestfrequency

Repeat lipase if
pancreatitis suspected

Risk of hepatic failure
is highest in first 6
months of treatment

24-hour urine
for protein andcreatinine clearance
if proteinuria, marked
polyuria or change inserum creatinine

Comments

Side effects of mood stabilizers and routine laboratory monitoring before and during pharmacotherapy (Birmaher & Axelson,

BMI: body max index; BUN: blood urea nitrogen; TSH: thyroid stimulating hormone; AST: aspartate aminotransferase; ALT: alanine aminotransferase; CBC: complete blood count; HDL:
high density lipoprotein; LDL: low density lipoprotein; AIMS: Abnormal Involuntary Movement Scale; PRN: as needed.
1
Initially, regular blood tests are required to check serum level. Once a desired and stable level is achieved, the other tests are to check serum levels and other parameters (e.g., renal andthyroid function).

Valproate

Bipolar disorder

Lithium

Table E.2.4
2005).

IACAPAP Textbook of Child and Adolescent Mental Health

19

E.2

Dizziness
AtaxiaHeadache
TremorBlurred vision, diplopia,

•
•
•
•
•

•
•
•

Nausea, vomiting
Clumsiness, dizziness
Nystagmus
Sedation
Blurred vision, diplopia,
photosensitivity
Cognitive dulling
AtaxiaCYP450 enzymeinduction (increased
clearance of drugs
metabolized byhepatic cytochrome
system, including oral
contraceptives)

•
•
•
•
•

Common

•

•
•

•
•

•
•
•
•

Rash
Nausea,vomiting
AtaxiaCognitive
dulling
Confusion

Hyponatremia
Rash
Confusion
Leukopenia

Uncommon

Seriousdermatologicalreactions
AnemiaAnticonvulsant
hypersensitivity
syndrome

•
•
•

•

•
•

•
•
•

Seriousdermatologicalreactions
Agranulocytosis
Aplastic anemia
Atrioventricular
block,
arrhythmias
Hepatitis
Renal
dysfunction
Anticonvulsant
hypersensitivity
syndrome

•

Rare

•

•

•
•

•

CBC withdifferential &platelet count
AST, ALTCBC withdifferential &platelet count
AST, ALT
SodiumBaseline tests

•

•

•

•
•

•

•

Lamotrigine levelis not suggested
but may guidetreatment
CBC withdifferential &platelet count
AST, ALT

Carbamazepine
level
CBC withdifferential &platelet count
AST, ALT
SodiumFollow-up tests

•

•

•

Every 3-6
months

1 & 3-4 weeks1
after dosechange and
PRN
With bloodlevels after
dose change
and then every
3-4 months

Test frequency

Clear instruction
should be given
about how to
avoid skin rash(e.g., avoiding sun
burn, not changing
lotion, shampoo, or
detergent) and when/
how to reach doctor
when rash occurs

Check labs if
unexplained
fever, sore throat,
lymphadenopathy orsevere fatigue

Comments

BMI: body max index; BUN: blood urea nitrogen; TSH: thyroid stimulating hormone; AST: aspartate aminotransferase; ALT: alanine aminotransferase; CBC: complete blood count; HDL:
high density lipoprotein; LDL: low density lipoprotein; AIMS: Abnormal Involuntary Movement Scale; PRN: as needed.
1
Initially, regular blood tests are required to check serum level. Once a desired and stable level is achieved, the other tests are to check serum levels and other parameters (e.g., renal andthyroid function).

Lamotrigine

Bipolar disorder

Carbamazepine

Table E.2.4 (Continuation)

IACAPAP Textbook of Child and Adolescent Mental Health20

Bipolar disorder

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•
•

•

•
•

Weight gain
Posturalhypotension
Extrapyramidal
symptoms
Dizziness
Sedation

Common

•
•
•

•

•
•
•
•

•

Hyperglycemia,
hypercholesterolemia,
increased triglycerides,
diabetes
Hyperprolactinemia
RashPhotosensitivity
Nausea, diarrhea,
dyspepsia, constipation
Elevated serumtransaminases
Urinary difficulties
Sexual dysfunction
Cognitive dulling

Uncommon

•
•

•

•

Tardive
dyskinesia
Neuroleptic
malignantsyndrome
SeizureHepatic failure

Rare

•

•
•

•
•

GlucoseTriglycerides, totalcholesterol,HDL,LDLAIMSHeight, weight,
BMI, waist
circumference
EKG (forziprasidone)

Baseline tests

•

•
•

•
•

GlucoseTriglycerides, totalcholesterol,HDL,LDLAIMSOther tests asnecessary (e.g.,
EKG)
Height, weight,
BMI, waist
circumference

Follow-up tests•

Every 3-6
months and
PRN

Test
frequency

Comments

BMI: body max index; BUN: blood urea nitrogen; TSH: thyroid stimulating hormone; AST: aspartate aminotransferase; ALT: alanine aminotransferase; CBC: complete blood count; HDL:
high density lipoprotein; LDL: low density lipoprotein; AIMS: Abnormal Involuntary Movement Scale; PRN: as needed.

Antipsychotics

Table E.2.4 (continuation)

IACAPAP Textbook of Child and Adolescent Mental Health21IACAPAP Textbook of Child and Adolescent Mental Healthfamily members are aware of the initial symptoms of serious side effects and how tocontact the doctor if they occur. However, it is controversial whether this reduces
the risk of serious adverse events.
There is a warning issued by the US FDA in 2008 about the risk forincreased suicidality associated with use of anticonvulsant medications (Aranaet al, 2010). Although other studies do not report an increased suicide risk with
anticonvulsants, patients (and families) should be informed about this risk andstrategies to deal with it discussed.
Valproate has been associated with polycystic ovary syndrome. Baseline
menstrual history and a gynecological consultation in any female who develops
significant changes in her menstrual cycle and/or hirsutism while on this medicationis required.
Carbamazepine induces the metabolism of other medications (e.g., oral
contraceptives) as well as its own metabolism and may decrease the blood level andreduce its effectiveness and that of other medications.
Oxcarbazepine, an analogue of carbamazepine, may not induce hepatic
enzymes and does not require blood level monitoring, but may cause other side
effects such as dizziness, nausea, somnolence, diplopia, fatigue, and rash.
Lamotrigine is usually well tolerated, with relatively low risk for weightgain and sedation. However, particularly when the dose is increased rapidly, it may
cause serious dermatological reactions such as Stevens-Johnson syndrome or toxic
epidermal necrolysis. Treatment should be suspended immediately if a new rashappears. Also, lamotrigine should be reinitiated from the starting dose of 12.5 or
25 mg/day if it is stopped for 5 days or more. The rate of serious dermatologicalreactions may be reduced by current dosing recommendations, that is, to prescribe
small amounts with gradual escalation (e.g., 25 mg/day in ≥ 12 years old adolescentswith dose increases of 25 mg every two weeks given in a twice a day regime until
100 mg/day is reached), especially if valproate is used concomitantly (lamotrigine
dose increases should be halved when in this combination because of a synergistic
drug interaction with valproate which increases lamotrigine levels); this increases
the risk of rash significantly. Note that it may take 6 to 8 weeks to achieve atherapeutic level because of this slow titration schedule.

Click here to see the FDA
approval status and quality of
research evidence for moodstabilizers and lithium.

Weight loss has been reported with topiramate when combined with SGAs(e.g., to counterbalance the weight gain side effect of SGAs). However, topiramate
is not recommended for mood symptoms of BD.
SGAs
There are common side effects of SGAs as listed in Table 5, but there aredifferences between them, such as in extrapyramidal symptoms, prolactin secretion,
and weight gain. Olanzapine and risperidone are associated with higher weightgain while lurasidone and ziprasidone with lower. The metabolic effects (e.g.,increased weight, glucose and lipids) of SGAs are of substantial concern especiallywhen they are used in youth over extended periods. Research suggests that weightgain is greater in youth relative to adults and in those in a SGA and mood stabilizer
combination (Correll et al, 2010). See Table E.2.5) Click here to access practicalmonitoring tables.

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IACAPAP Textbook of Child and Adolescent Mental Health

If a patient exhibits significant weight gain, a more thorough investigation of
metabolic status and a re-evaluation of the risk-benefit ratio of continuing with thecurrent SGA are indicated. As mentioned above, consultation with a pediatrician
and nutritionist and referral to a weight management clinic is advisable to manage
weight gain or risk for metabolic syndrome before considering adjunct medications.
Available data suggest that adjunct metformin (and lifestyle interventions) may be
helpful in some adults and adolescents (Morrison et al, 2002; Praharaj et al, 2011;
Walkup & Cottingham, 2017; Zheng et al, 2019). In addition, although rare,
the SGAs may cause extrapyramidal symptoms, tardive dyskinesia and neuroleptic
malignant syndrome, and the youth needs to be evaluated at baseline and routinely
for abnormal movements. Baseline EKG is not a routine test but may be necessary
to rule out cardiac problems including QT prolongation if there is history of
cardiac problems in the child or family or if ziprasidone or concomitant stimulant
use is considered.
AntidepressantsIn youth, selective serotonin reuptake inhibitors (SSRIs) may be helpful forthe treatment of bipolar depression, but some youth on SSRIs experience manic
switch. SSRIs and other antidepressants can trigger mania, hypomania, mixed
episodes or rapid cycling, particularly when used without concomitant moodstabilizer treatment. About 5-10% of youths being treated with SSRIS/SNRIs
may become disinhibited (Carlson & Mick, 2003). These symptoms should not
be confused with hypomanic and manic symptoms. The disinhibition subsides
1-2 day after discontinuing the antidepressants. Families and youth should
be informed about risks versus benefits of using antidepressants (including thewarnings of US and British regulatory agencies about the small—1 to 3 per 100
persons—but significant increased risk for suicide with antidepressants) and, in
addition to suicidality, close attention should be paid to possible increases or onsetof agitation and serotonin syndrome (especially when combined with lithium).
A safety plan including how to manage these risks should be discussed with theTable E.2.5

Parameters in monitoring second-generation antipsychotic use.
At the beginning

Parameter

Baseline

4
weeks

8
weeks

12
weeks

Quarterly









Annually

Personal history



Family history



Weight (BMI)

Waist circumference

Blood pressure







Fasting blood glucose







Fasting lipid profile

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Every
5 Years

23

IACAPAP Textbook of Child and Adolescent Mental Healthyouth and the family and, if indicated, the SSRIs or other antidepressants should
be started in small doses, after stabilization of manic or hypomanic symptoms withmood stabilizers (Birmaher and Axelson, 2005). Tricyclic antidepressants should
not be used since there is no evidence that they are clinically effective and are very
toxic on overdose, an ever-present risk in depressed adolescents.

PSYCHOSOCIAL TREATMENTS
Supportive psychotherapy is necessary for all BD youth and their families.
Specific psychosocial treatments have been developed to help with psychoeducation,
manage acute manic and depressive symptoms, improve coping skills and adherence
to treatment, and manage comorbid conditions. In addition, they may help withpreventing recurrences. Parents are engaged in their youth’s therapy and referred totreatment if necessary (Birmaher & Axelson, 2005). Also, psychosocial treatmentsthat have been found efficacious for the treatment of comorbid conditions such as
oppositional behaviors, substance abuse, and anxiety disorders are indicated before
initiating pharmacotherapy for these conditions. Thus far, there are several lines ofoverlapping psychosocial therapies for BD youth and their families, designed to fit
specific age groups and methods of intervention:

Child and Family Focused Cognitive Behavior Therapy
These therapies were specifically designed for 8-18 year-olds (West et al,2007). In addition to focusing on the identified child, it includes intensive workwith parents to support them in developing an effective parenting style and to meettheir own therapeutic needs. It integrates the principles of reward-based CBT withinterpersonal psychotherapy, with an emphasis on empathic validation. It consistsof 12, 60-minute weekly sessions over 3 months dealing with multiple domains—individual, family, peer, and school. The key components are summarised by theacronym RAINBOW (West et al, 2007):• Routine,• Affect regulation,• I can do it,• No negative thoughts and live in the now,
• Be a good friend/balanced lifestyle for parent,• Oh—how can we solve this problem, and• Ways to get support.
Data from open studies and a RCT suggest this therapy is associatedwith improvement in functioning, mood symptoms, and treatment adherence(Weinstein et al, 2015; West et al, 2014).

Multi-Family Psychoeducation Groups and Individual Family
Psychoeducation
Fristad et al (Fristad, 2006) has developed multi-family psychoeducationgroups and individual family psychoeducation as adjunctive treatments forbipolar and depressive spectrum youth. The goals are to increase knowledge andunderstanding of BD and its treatment, improve management of symptoms

Bipolar disorder

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IACAPAP Textbook of Child and Adolescent Mental Healthand associated conditions, improve communication and problem-solving skills,
and increase the child and family’s sense of support in dealing with the illness,emphasizing psychoeducation on the role of medication and coping strategies. It
consists of 24, 50-minute individual sessions, 20 are manual-driven and 4 are to
be used for crisis management or additional practice.

Family Focused Therapy
Miklowitz et al (2011) developed a manualized version of family focused
therapy specifically for adolescents with BD. It has the primary goal of reducing
symptoms through increased awareness of how to cope with the disorder,of decreasing levels of familial expressed emotion, and of improving family
problem-solving and communication skills. It has three treatment components:
psychoeducation, communication enhancement training, and problem-solving
skills training. In a 2-year randomized control trial, compared to an enhanced
treatment group, adolescents who received this therapy recovered earlier fromdepression, spent less time in depressive episodes, and reported lower depression
severity scores. However, a more recent randomized trial failed to show advantagesof intensive psychotherapy combined with best-practice pharmacotherapy vs. brief
psychotherapy and pharmacotherapy (Miklowitz et al, 2014).

Dialectical Behavior Therapy
Goldstein et al (2007) adopted dialectical behavior therapy—a treatment
initially designed for adults with borderline personality disorder—for the treatmentof adolescents. The adapted intervention consists of 6 months of weekly 60-minutesessions followed by another 6 months of bimonthly sessions. A RCT showedthat adolescents receiving dialectical behavior therapy demonstrated less severe
depressive symptoms and greater likelihood of improvement in suicidal ideation
when compared with psychosocial treatment as usual (Goldstein et al, 2015).

Interpersonal and Social Rhythm Therapy
Hlastala et al (2010) adapted interpersonal and social rhythm therapy
for adolescents with BD. They suggest that psychosocial stressors precipitate
or exacerbate bipolar episodes through their ability to disrupt social and sleep
routines. The emphasis is on addressing interpersonal functioning deficits andmanaging affective symptoms to reduce their negative influence on psychosocial
functioning. A pilot study of 16 to 18 sessions over 20 weeks reported significant
improvements in manic, depressive, and general psychiatric symptoms.

Click on the picture to visit
the AACAP’s resource centerto access reading materials
such as “facts for families”
and “frequently asked
questions” and to watcha short interview with Dr
Birmaher

Recent studies have started to explore the potential benefit of early
psychosocial intervention to ameliorate or even prevent the onset and progressionof symptoms in youth at high risk for BD. Goldstein and colleagues modified
interpersonal and social rhythm therapy for the adolescent offspring of parents
with BD who had not yet developed BD. An open study showed that it was
feasible and acceptable for this group and detected an improvement in sleep andcircadian patterns (Goldstein et al, 2014). A RCT suggested some benefits in atreatment group (Goldstein et al, 2018).

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IACAPAP Textbook of Child and Adolescent Mental Health

CONTINUATION AND MAINTENANCE TREATMENT
Relatively few studies have examined continuation and/or maintenancetreatment of BD in youth. Available evidence in consensus guidelines varies (Parker
et al, 2017). During the continuation phase of treatment, which starts soon after
the acute treatment of depression or mania/hypomania to prevent relapse andrecurrence, clinicians usually continue the effective treatment interventions that
helped the acute mood episode. After the acute treatment, clinicians should focus
on treating the “syndromal” or “subsyndromal” mood symptoms because these
symptoms increase the risk of relapse. To prevent relapses, the medications that
helped during the acute phase need to be continued for at least 6-12 months. One
recurrent mood episode may suggest increasing the maintenance phase to 12-24
months; subsequent recurrent episodes would require discussion with family andyouth about longer duration of medication treatment for prevention of further
episodes. Thus, the duration of treatment will usually depend on the severity
and length of the illness, comorbid conditions that impair functioning, moodswings, exposure to stress, availability of psychosocial interventions at home andschool, parental psychopathology, social supports, and other family and social
circumstances.
Lithium, lamotrigine (especially for depression), SGAs and, to a lesser
extent, valproate, are effective in preventing new episodes in adults. In youth,
lithium and divalproex appear to be similarly effective (e.g., Findling et al, 2019).
While the optimal duration of psychosocial treatments for pediatric BD
has not been established, continuing psychosocial interventions for subthresholdmood symptoms may be helpful (Miklowitz et al, 2011). It is reasonable to provide
ongoing psychosocial support, crisis management and therapy booster sessions as
appropriate (Birmaher & Axelson, 2005; Goldstein et al, 2017).

CULTURAL PERSPECTIVES
Many professionals do not have access to non-English scientific literature
and we largely don’t know how BD youth around the world is being diagnosed andtreated. Historically, several factors have made the diagnosis of bipolar disorder inchildhood difficult. These include lack of awareness, diagnostic confusion, clinicalbias against the diagnosis of mania in children, low prevalence, symptom overlap
between bipolar disorder and other more common childhood-onset psychiatricdisorders, developmental constraints, and variability in clinical presentation.
Stigma remains a big problem. Many clinicians around the world arestill skeptical about persistent non-episodic manic symptoms, ultra-rapid mood
cycling, and BD diagnosis in preschool children (Diler, 2007). However, a metaanalysis of epidemiological studies suggests that rates of BD-I in youth in the US
and outside the US are similar (Van Meter et al, 2011).
Formal training in child psychiatry exists in only a few countries andcountries where it actually exists have shortages of child psychiatrists (e.g., there
are around 150 doctors trained in child psychology and psychiatry in China and100 in Japan). In addition, trained allied mental health professionals, such as social
workers, clinicians, nurses, and case workers are lacking in many countries (Diler,
2007).

Bipolar disorder

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In 1959, Shingawa
described mania in youth
in Japan as “Tendenciesof hypomania, rash andfrivolous words andbehavior, appearance ofproblem behavior, andchange from introversion
to extroversion during
periods of remission, leadon to ultimate transition
into a positive personality
exhibiting activeness,cheerfulness, andextroversion as a newstable personality uponcessation of the biphasic
fluctuations.”

26

IACAPAP Textbook of Child and Adolescent Mental Health

Using different diagnostic classification systems also have clinicalimplications. Professionals who use the ICD tend to give one diagnosis whereas
multiple comorbid diagnoses, especially in youth with BD, are almost the rule
when using the DSM. With some exceptions (e.g., the Chinese classification of
psychiatric disorders), clinicians and researchers around the world use the DSM
and not the ICD to diagnose BD in children but it is not known if the expressionof some manic symptoms is different or if some symptoms are more or less often
present in some cultures (Diler, 2007).
There are case reports or studies of BD in youth around the world datingback to the 1900s. Case series of adolescent onset BD appeared in the local
psychiatric literature more than 100 years ago in China. Several case reportsof children and adolescents with BD appeared in the Japanese literature in the
1950s, including a 10-year old child treated with ECT for depression and mania(Diler, 2007). However, in many countries, research in BD followed the increasein this diagnosis in the US, initially through case reports, but more recently they
include epidemiologic, high-risk offspring studies, and biological (e.g., genetic,
neuroimaging) studies that report findings similar to those in the US (Van Meteret al, 2011; Diler, 2007). In contrast with US findings, research studies from
India—that examined bipolar youth who had never been on medication—foundrelatively lower ADHD comorbidity. However, the course was similar, i.e., highrates of recovery followed by relapses (Diler, 2007).
Some countries report less traditional treatments. For example, in China
the first steps are to normalize the child’s social environment, regulating thebalance between active exercise/playing and mental stimulation (e.g., by reducing
overstimulation from TV, movies, and video games) as well as providing the childwith freshly prepared food (limiting the intake of sugar, dairy, foods reach insalicylic acid, and food preservatives) and supplementation with zinc and iron.
Some clinics in China may prescribe psychiatric medications while others may
consider acupuncture and herbal remedies. In India the practice at the inpatient
services is to admit children with their caregivers who stay with the children during
the entire hospitalization. Data from clinicians and researchers around the world
would progress or even challenge our understanding of pediatric BD and help us
integrate cultural and geographical aspects of this condition (Diler, 2007).

Click here to viewinternational variations in
the diagnosis of childhood
onset bipolar disorder

CONCLUSION
Despite the controversies, it is clear that, taking into account thedevelopmental stage, it is possible to diagnose BD in children and adolescents.
However, diagnosis may be cumbersome, especially in younger children and thosewith comorbid disorders (e.g., ADHD). Pediatric BD is associated with severe
psychosocial consequences and increased risk for suicidality and substance abuse,stressing the need for prompt identification and treatment.
BD in youth is not limited to a few countries but a global problem.
Clinicians around world are encouraged to share their experiences through casereports or clinical studies. This will help to incorporate cultural aspects of clinicalpresentations. Compared to 15 or 20 years ago, we now know more about effective
screening and diagnosis, and there are more data to guide medication treatment aswell as psychosocial interventions. However, most of the treatment studies focus

Bipolar disorder

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27

IACAPAP Textbook of Child and Adolescent Mental Healthon the acute phase. More research is needed in the acute treatment of bipolar
depression and of comorbid conditions, such as ADHD and anxiety disorders. We
also need to learn more about treatment of subsyndromal presentations and on
how to prevent recurrences.
High risk studies are important for identifying early presentations that canguide prevention. Preliminary studies investigating disease and treatment specificbiomarkers are promising, but longitudinal studies (combined with ecologicalmonitoring using mobile sensors) in larger samples are needed to better understandcore pathophysiological processes and individualized treatment/prevention options
in youth with and at-risk for BD.
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IACAPAP Textbook of Child and Adolescent Mental Health

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Disorders 19:524-543.
Goldstein TR, Axelson DA, Birmaher B et al (2007). Dialecticalbehavior therapy for adolescents with bipolar disorder:
a 1-year open trial. Journal of the American Academy ofChild & Adolescent Psychiatry 46:820-830.
Goldstein TR, Fersch-Podrat R, Axelson DA et al (2014).
Early intervention for adolescents at high risk forthe development of bipolar disorder: pilot study ofInterpersonal and Social Rhythm Therapy (IPSRT).
Psychotherapy 51:180-189.
Goldstein TR, Fersch-Podrat RK, Rivera M et al (2015).
Dialectical behavior therapy for adolescents withbipolar disorder: results from a pilot randomized trial.
Journal of Child & Adolescent Psychopharmacology
25:140-149.
Goldstein TR, Merranko J, Krantz M (2018). Early intervention
for adolescents at-risk for bipolar disorder: A pilot
randomized trial of Interpersonal and Social Rhythm
Therapy (IPSRT). Journal of Affective Disorders
235:348-356.
Hafeman D, Bebko G, Bertocci MA et al (2017a). Amygdalaprefrontal cortical functional connectivity during
implicit emotion processing differentiates youth
with bipolar spectrum from youth with externalizing
disorders. Journal of Affective Disorders 208:94-100.
Hafeman DM, Merranko J, Axelson D et al (2016). Toward
the definition of a bipolar prodrome: dimensional
predictors of bipolar spectrum disorders in at-riskyouths. American Journal of Psychiatry 173:695-704.
https://ajp.psychiatryonline.org/doi/full/10.1176/appi.
ajp.2015.15040414
Hafeman DM, Merranko J, Goldstein TR et al (2017b).
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Henry DB, Pavuluri MN, Youngstrom E et al (2008). Accuracyof brief and full forms of the Child Mania Rating
Scale. Journal of Clinical Psychology 64:368-381.

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Hlastala SA, Kotler JS, McClellan JM et al (2010). Interpersonaland social rhythm therapy for adolescents with bipolar
disorder: treatment development and results from an
open trial. Depression & Anxiety 27:457-464.
Holtzman JN, Miller S, Hooshmand F et al (2015). Childhoodcompared to adolescent-onset bipolar disorder has
more statistically significant clinical correlates. Journalof Affective Disorders 179:114-120.
Ikeda M, Saito T, Kondo K et al (2018). Genome-wide
association studies of bipolar disorder: A systematic
review of recent findings and their clinicalimplications. Psychiatry and Clinical Neurosciences
72:52-63.

Nivoli AM, Colom F, Murru A et al (2011). New treatment
guidelines for acute bipolar depression: a systematic
review. Journal of Affective Disorders 129:14-26.
Pan LA, Goldstein TR, Rooks BT et al (2017). The relationshipbetween stressful life events and axis i diagnoses
among adolescent offspring of probands with bipolarand non-bipolar psychiatric disorders and healthy
controls: The Pittsburgh Bipolar Offspring Study(BIOS). Journal of Clinical Psychiatry 78: e234-e243.
Parker GB, Graham RK, Tavella G (2017) Is there consensus
across international evidence-based guidelines for the
management of bipolar disorder? Acta Psychiatrica
Scandinavica 135:515-526.

Kowatch RA, Youngstrom EA, Danielyan A et al (2005). Review
and meta-analysis of the phenomenology and clinicalcharacteristics of mania in children and adolescents.
Bipolar Disorders 7:483-496

Pavuluri MN, Henry DB, Devineni B et al (2006a). Childmania rating scale: development, reliability, andvalidity. Journal of the American Academy of Child &Adolescent Psychiatry 45:550-560.

Kozloff N, Cheung AH, Schaffer A et al (2010). Bipolar disorderamong adolescents and young adults: results from anepidemiological sample. Journal of Affective Disorders
125:350-354.

Pavuluri MN, Schenkel LS, Aryal S et al (2006b).
Neurocognitive function in unmedicated manic
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Leibenluft E, Charney DS, Towbin KE et al (2003). Defining
clinical phenotypes of juvenile mania. American
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Pavuluri MN, West A, Hill SK et al (2009). Neurocognitive
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healthy youths. Journal of the American Academy ofChild & Adolescent Psychiatry 48:299-307.

Liu HY, Potter MP, Woodworth KY et al (2011). Pharmacologic
treatments for pediatric bipolar disorder: a review
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McClellan J, Kowatch R, Findling RL (2007). Practiceparameter for the assessment and treatment of children
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46:107-125. https://www.jaacap.org/article/S08908567(09)61968-7/fulltext
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Perlis RH, Dennehy EB, Miklowitz DJ et al (2009).
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Pieter Bruegel the Elder - The Peasant Dance

Bipolar disorder

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IACAPAP Textbook of Child and Adolescent Mental HealthAppendix E.2.1

Bipolar disorder

E.2

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IACAPAP Textbook of Child and Adolescent Mental HealthAppendix E.2.2

Bipolar disorder

E.2

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IACAPAP Textbook of Child and Adolescent Mental HealthAppendix E.2.3

Joseph M Rey & Rasim Somer Diler
SELF-ASSESSMENT EXERCISES(Only one answer is correct)
E.2.1 Which one of these factors
increases the risk of bipolar
disorder the most?
A
B
C
D
E

Having a father with bipolar disorder
Having a mother who abuses alcohol
History of sexual abuse
Having had a previous major
depressive episodeA personal history of aggressive
behavior

E.2.2

The main difference between
bipolar-I and bipolar II is that:A

Bipolar I cannot be diagnosed until
the individual is a young adult
Bipolar-II lacks full-blown manic
episodesBipolar-I has rapid cycles
Bipolar-II does not have major
depressive episodes
Episodes are longer I bipolar-II

B
C
D
E
E.2.3

A distinct period of abnormallyand persistently elevated,
expansive, or irritable moodand abnormally and persistently
increased activity or energy level,
which lasts most of the day, nearly
every day, meets criteria for a
manic episode if it:

A
B
C
D
E

Lasts four or more days
Lasts seven or more days
Lasts more than 14 days
Has a grandiose content
Has a sexualized content

Bipolar disorder

E.2

E.2.4 Janet is 13 years of age. In
the 4 to 5 years prior to her
visit, multiple mental healthevaluations and treatments
had been undertaken; however,
little clinical improvement had
been noticed. She had been
diagnosed with ADHD. Her current
assessment was triggered by her
behavior the previous 10 days:
not sleeping at all, spending
the nights cleaning her room,
she had unrealistic projects
like becoming a rock star, wasunable to remain seated, could
not concentrate, was irritable, andspoke non-stop, but there wasno suggestion of hallucinations
or delusions. Nevertheless, she
was so disturbed that she wasadmitted to hospital. Which one of
the following would be your firstmanagement?
A
B
C
D
E

Observing the child
Individual psychotherapy
Methylphenidate
A second generation antipsychotic
Mindfulness therapy

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IACAPAP Textbook of Child and Adolescent Mental Health

E.2.5

A
B
C
D
E

E.2.6

A
B
C
D
E

Irritability is a very common
symptom in children andadolescents. However, it issuggestive of a bipolar disorder
only if it:
Is explosive or severe
Responds to lithium treatment
Happens after school
Begins or significantly increases
in intensity in conjunction with thepresence of other manic symptoms
Does not respond to behavioral
management

An adolescent, who was being
treated with antidepressantsbecause of suffering from major
depression, developed mania.
Which of these interventions
would you implement first?
Start treatment with lithium
Start treatment with a second
generation antipsychotic
Admit to hospital
Stop antidepressantsLower the antidepressant dose

E.2.8

A key criterium for the diagnosisof bipolar depression is:A

The presence of biological symptoms(melancholia)
Early morning wakening
Mood congruent delusions
History of mania
Suicidal thoughts

B
C
D
E

E.2.9

Comorbid disorders are veryfrequent in youth with bipolar
disorder. In general, management
wise, it is recommended to first:

A

Clarify which one is the primarydisorderTreat both disorders concurrently
Treat the condition that is likely
to show a quicker response (e.g.,
ADHD)
Treat the comorbid condition
Stabilize the bipolar symptoms

B
C
D
E

E.2.10The US FDA issued a warning in2008 about the risk for increased
suicidality associated with the useof anticonvulsant medications.
Subsequently some other studies
did not report an increased suicide
risk with these drugs. How would
you deal with this in relation topatients and families? I would:A
BC

Not prescribe anticonvulsantsNot tell anything.
Only tell this to the parents but not
the child
Inform them about this risk anddiscuss strategies to deal with itTell them this fear is unfounded

E.2.7 The target blood level for lithium
in the acute treatment of bipolar
disorder should be (mEq/L):
A
B
C
D
E

0.4 to 0.7
0.8 to 1.1
1.2 to 1.4
1.5 to 1.8
1.9 to 2.3

DE

Bipolar disorder

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IACAPAP Textbook of Child and Adolescent Mental Health

A.2.1

Answer: A

A.2.2

Answer: B

A.2.3

Answer: B

A.2.4

Answer: D

A.2.5

Answer: D

A.2.6

Answer: D

A.2.7

Answer: B

A.2.8

Answer: D

A.2.9

Answer: E

A.2.10 Answer: D

Bipolar disorderE.237