Reviews and Overviews

Mechanisms of Psychiatric Illness

Severe Mood Dysregulation, Irritability, and the

Diagnostic Boundaries of Bipolar Disorder in Youths

Ellen Leibenluft, M.D. In recent years, increasing numbers of and pathophysiology. Longitudinal data
children have been diagnosed with bipo- in both clinical and community samples
lar disorder. In some cases, children with indicate that nonepisodic irritability in
unstable mood clearly meet current di- youths is common and is associated with
agnostic criteria for bipolar disorder, and an elevated risk for anxiety and unipo-
in others, the diagnosis is unclear. Severe lar depressive disorders, but not bipolar
mood dysregulation is a syndrome de- disorder, in adulthood. Data also suggest
fined to capture the symptomatology of that youths with severe mood dysregula-
children whose diagnostic status with re- tion have lower familial rates of bipolar
spect to bipolar disorder is uncertain, that disorder than do those with bipolar disor-
is, those who have severe, nonepisodic ir- der. While youths in both patient groups
ritability and the hyperarousal symptoms have deficits in face emotion labeling
characteristic of mania but who lack the and experience more frustration than do
well-demarcated periods of elevated or normally developing children, the brain
irritable mood characteristic of bipolar mechanisms mediating these pathophysi-
disorder. Levels of impairment are com- ologic abnormalities appear to differ be-
parable between youths with bipolar tween the two patient groups. No specific
disorder and those with severe mood treatment for severe mood dysregulation
dysregulation. An emerging literature currently exists, but verification of its
compares children with severe mood dys- identity as a syndrome distinct from bi-
regulation and those with bipolar disor- polar disorder by further research should
der in longitudinal course, family history, include treatment trials.
(Am J Psychiatry 2011; 168:129–142)

T he past decade has seen a dramatic increase in focus

on pediatric bipolar disorder as the number of children
tify English-language publications on these two topics,
comprehensive literature searches were conducted that
receiving the diagnosis has escalated (1–3). Discussion included all articles on pediatric bipolar disorder or irrita-
has centered on the diagnostic boundaries of bipolar bility published in major psychiatric journals over the past
disorder in children as compared with adults. Among 20 years. The reference lists of these articles were reviewed
the many questions that have arisen is whether nonepi- to identify other papers on these two topics. Because the
sodic severe irritability is a developmental presentation of publications comparing youths with severe nonepisodic
mania. To evaluate this possibility, we can use longitudinal irritability with those with classic presentations of bipo-
designs to test whether youths with this phenotype grow lar disorder emerged from the National Institute of Men-
up to display classic episodic bipolar disorder. In addition, tal Health (NIMH), the source of the present article, this
using cross-sectional designs, we can recruit children who review necessarily focuses on these publications. Never-
already display the classic bipolar disorder phenotype and theless, relevant papers from other sources also are care-
compare them with children who have the proposed alter- fully considered.
native phenotype using validators such as parental history Although published data suggest that children with
and pathophysiologic measures. severe nonepisodic irritability do not suffer from bipolar
Both of these strategies are used in the research disorder, at least as it is classically defined, some research
described in this review. One component of the review groups maintain that it is nonetheless reasonable to apply
focuses on studies that contrast children from three a bipolar diagnosis to children with such a clinical presen-
groups: those with severe nonepisodic irritability, those tation (4–7). One important argument for this position is
with classic presentations of bipolar disorder, and those that children with severe nonepisodic irritability manifest
with no mental illness. A second component focuses on severe mood symptoms and are as severely impaired as
the clinical outcomes of nonepisodic irritability. To iden- those with classic bipolar disorder, but without a diagno-

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SEVERE MOOD DYSREGULATION, IRRITABILITY, AND BIPOLAR DISORDER IN YOUTHS

sis of bipolar disorder their access to the mental health in hypomania or mania and dysphoria or anhedonia [or,
services they need might be limited. I will argue, however, in children only, irritability] in depression) and 2) accom-
that because data suggest that children with severe non- panying behavioral, physical, and cognitive symptoms
episodic irritability do not suffer from bipolar disorder, (e.g., changes in sleep, appetite, activity, and so on). The
rather than broadening the definition of bipolar disorder accompanying symptoms are considered components of
to include them, the issue of access to appropriate treat- a mood episode only if they begin at approximately the
ment may be better addressed through efforts to empha- same time as the mood disturbance or if they predate the
size the seriousness of chronic irritability as a presenting mood disturbance but worsen concurrently with it. (For a
symptom in children and to support research designed to detailed discussion of the clinical assessment of potential
delineate its pathophysiology and treatment. manic episodes and severe mood dysregulation in chil-
Thus, while there is disagreement on whether the bipo- dren, see reference 8.)
lar diagnosis should be applied to youths with severe Within the past 15 years, researchers have suggested
nonepisodic irritability, there is widespread agreement that mania presents differently in youths than in adults:
that such irritability and classic bipolar disorder are both in youths it presents not as distinct euphoric or irritable
common clinical presentations in children and merit sig- episodes but as persistent, nonepisodic, severe irritability
nificant investment in treatment and research. In DSM- (4–7). This marks an important deviation from the classi-
IV, a diagnosis of bipolar disorder in children, as in adults, cal conceptualization of bipolar disorder and is inconsis-
requires the presence of a well-demarcated period of tent with the DSM-IV criterion A requirement of a “distinct
elevated or irritable mood along with associated symp- period” of abnormally elevated, expansive, or irritable
toms. Research to test whether nonepisodic irritabil- mood.
ity is a developmental presentation of bipolar disorder To understand the public health implications of this
began with the description of a syndrome called “severe view, it is important to note the overlap between symp-
mood dysregulation.” Longitudinal, family-based, and toms of mania and those of attention deficit hyperactivity
pathophysiologic studies then followed. This work dem- disorder (ADHD) (15). Distractibility, pressured speech,
onstrates important differences between severe mood psychomotor agitation, racing thoughts, and increased
dysregulation and bipolar disorder, which in turn carry goal-directed activity are all diagnostic criteria of mania
implications for therapeutics and nosology. that also occur in ADHD. Furthermore, while irritability
is not a diagnostic criterion for ADHD, temper outbursts
Diagnosing Bipolar Disorder in Youths: and other deficits in self-regulation are often seen in chil-
The Controversy dren with ADHD (16, 17). Also, the prevalence of ADHD in
youths (1.9%) is considerably higher than that of episodic
Data from both inpatient and outpatient settings indi- DSM-IV bipolar disorder (0.1%) (18). Therefore, viewing
cate a recent and marked increase in the rate at which nonepisodic irritability as a developmental presentation
youths have received the diagnosis of bipolar disorder in of mania could markedly affect prevalence estimates of
the United States. Between 1994 and 2003, the percent- bipolar disorder; the rediagnosis of even a relatively small
age of visits for a mental disorder assigned the diagno- percentage of children with ADHD as having bipolar dis-
sis of bipolar disorder increased from 0.42% to 6.67% in order would result in significantly higher rates of bipolar
youths (2). Similarly, between 1996 and 2004, the rate of disorder. As discussed later, such rediagnosis could also
children with a hospital discharge diagnosis of bipolar have significant treatment implications. Therefore, it is
disorder increased from 1.3 to 7.3 per 10,000, and dis- important to test systematically the hypothesis that non-
charges of adolescents with bipolar disorder increased episodic irritability is a form of mania.
400% (1).
Such trends could result from a true prevalence increase,
better case identification, or new conceptualizations of
Research Strategy
pediatric bipolar disorder. The recent child psychiatry lit- In the absence of validated bipolar disorder biomarkers,
erature contains considerable discussion on the appropri- how does one test whether severe nonepisodic irritabil-
ate techniques and criteria for diagnosing bipolar disorder ity is a developmental presentation of mania? To address
in youths (4, 7–14). One particularly pressing question this question, my colleagues and I adopted two research
concerns whether youths with severe irritability but with- strategies. The first involves longitudinal studies: if non-
out distinct manic episodes exhibit a developmental pre- episodic irritability is a developmental presentation of
sentation of mania. bipolar disorder, one would expect youths with this phe-
Since well before the DSM era, bipolar disorder has notype, over time, to develop episodic mania, hypomania,
been conceptualized as an illness characterized by dis- or bipolar disorder not otherwise specified. The second
crete episodes of depression and hypomania or mania, strategy involves cross-sectional studies comparing family
with an episode consisting of 1) a distinct change in mood history and pathophysiology in youths with the alterna-
from baseline (i.e., elevated, expansive, or irritable mood tive phenotype to 1) youths with clearly episodic bipolar

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 ELLEN LEIBENLUFT

disorder, diagnosed using criteria and techniques parallel scales (although see references 23–25), and normative
to those used in adults; 2) youths with psychopathology data are all sparse. In fact, DSM-IV provides no definition
other than mood disorders; and 3) youths with no psy- of irritability, despite the inclusion of this symptom as a
chopathology. Because research suggests that episodic criterion for at least six diagnoses in children (manic epi-
pediatric bipolar disorder exhibits a course similar to sode, oppositional defiant disorder, generalized anxiety
that of adult bipolar disorder (19–21), youths with clearly disorder, dysthymic disorder, posttraumatic stress disor-
episodic bipolar disorder provide an important standard der, and major depressive episode).
against which to test proposed alternative phenotypes. If To facilitate research on nonepisodic severe irritabil-
data from youths with episodic bipolar disorder and those ity and its relationship to bipolar disorder, my colleagues
with chronic severe irritability resemble each other but are and I (14) defined a syndrome termed “severe mood
distinct from data from youths with other forms of psy- dysregulation” (Figure 1). The syndrome captures the
chopathology and from healthy youths, a strong argument symptomatology of youths whose nosologic status vis-à-
can be made for the alternative phenotype being a form of vis bipolar disorder remains in doubt. In designing the
bipolar disorder. In the absence of such data, however, this criteria for severe mood dysregulation, our approach
argument cannot be supported. Alternatively, if data dif- was descriptive, drawing on available data and expert
ferentiate the classic bipolar disorder phenotype from the consultation. We did not claim to define a discrete diag-
other three groups, this would suggest that the alternative nosis; as with classic bipolar disorder, we expected that
phenotype is not a form of bipolar disorder. children with severe mood dysregulation would meet
Notably, questions about the nosologic status of non- criteria for other syndromes as well (e.g., oppositional
episodic irritability are phrased categorically here. How- defiant disorder). In defining severe mood dysregulation,
ever, it also is important to incorporate a dimensional we had five goals: 1) to operationalize severe irritability
perspective (22). As discussed later, data suggest that reliably, with a high threshold, far beyond that of any cur-
severe nonepisodic irritability in youths might be on a rent DSM-IV diagnosis; 2) to identify youths who are as
pathophysiologic continuum with both bipolar disorder severely impaired as those with bipolar disorder so that
and major depressive disorder. Nonetheless, categorical any observed differences between severe mood dysreg-
approaches are also important, since the decision to treat ulation and bipolar disorder could not be attributed to
with one intervention rather than another is categorical. differences in severity; 3) to require symptoms common
to mania and ADHD, since such symptoms were part of
the rationale for assigning the bipolar disorder diagnosis
Defining Severe Mood Dysregulation to children with severe chronic irritability; 4) to exclude
Questions about the appropriate criteria for pediatric preschoolers and patients whose symptoms did not
bipolar disorder highlight limitations in nosology and begin until adolescence, because irritability may fluc-
research. First, no DSM-IV category captures the symp- tuate during these developmental transitions; and 5) to
tomatology of children characterized primarily and exclude youths with even brief episodes of mania, such
fundamentally by severely impairing nonepisodic irri- as those meeting criteria for episodic bipolar disorder
tability. Indeed, the lack of a DSM-IV category for chil- not otherwise specified (26).
dren affected by such severe mood symptoms may have In severe mood dysregulation, irritability is defined as
contributed to the movement toward applying to them having two components: 1) temper outbursts that are
the diagnosis of bipolar disorder. This movement in turn developmentally inappropriate, frequent, and extreme;
could have contributed to rising rates of pediatric bipolar and 2) negatively valenced mood (anger or sadness)
diagnosis. between outbursts. The latter criterion is required in order
Other DSM-IV disorders do not accurately capture the to include youths with a persistent mood disorder rather
phenotype exhibited by severe irritability. While crite- than those who have temper outbursts but normal mood
ria for oppositional defiant disorder include “often loses between episodes. In practice, virtually all children with
temper,” “often touchy and easily annoyed by others,” severe mood dysregulation meet criterion 2 by virtue of
and “often angry and resentful,” nonirritable children can having persistently angry mood between outbursts. The
meet criteria for oppositional defiant disorder only on two-pronged definition of irritability that we employed
the basis of oppositional behavior. Furthermore, opposi- selects for youths with severe impairment, and other cri-
tional defiant disorder encompasses a wide range of clini- teria increase the likelihood of accomplishing this goal—
cal presentations in terms of severity. While irritability is symptoms must be severely impairing in at least one of
also a diagnostic criterion for major depressive disorder three contexts (home, school, or with peers) and at least
in youths, this disorder, like bipolar disorder, is defined as mildly impairing in a second. To ensure that significant
episodic. impairment is present and to operationalize chronic-
Second, diagnostic questions about pediatric bipolar ity, the syndrome must be present for at least 1 year with
disorder also highlight the relative paucity of research no more than 2 symptom-free months. And, to set clear
on irritability: operationalized definitions, reliable rating boundaries with bipolar disorder, youths with psychosis

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SEVERE MOOD DYSREGULATION, IRRITABILITY, AND BIPOLAR DISORDER IN YOUTHS

FIGURE 1. Research Diagnostic Criteria for Severe Mood Schizophrenia–Present and Lifetime Version (K-SADS-PL;
Dysregulationa
module available on request). The module is administered
by master’s- or doctoral-level clinicians who are trained
Inclusion criteria
to reliability (kappa=0.90), including in the distinction
1. Current age 7–17 years, with onset of the syndrome between severe mood dysregulation and bipolar disor-
before age 12. der. In the NIMH sample, the mean age at study entry is
2. Abnormal mood (specifically, anger or sadness), present 11.7 years, but parents report a mean age at onset nearly 7
at least half of the day most days, and of sufficient years earlier. The mean Children’s Global Assessment Scale
severity to be noticeable by people in the child’s
environment (e.g., parents, teachers, peers). (CGAS) (27) score is 45.8 (SD=6.9), compared with a mean
score of 46.5 (SD=12.4) for 107 youths with bipolar disor-
3. Hyperarousal, defined by at least three of the following:
insomnia, agitation, distractibility, racing thoughts or der recruited over the same period, indicating that youths
flight of ideas, pressured speech, and intrusiveness. with severe mood dysregulation are as severely impaired
4. Compared to his or her peers, the child exhibits as those with bipolar disorder. Approximately 60% of the
markedly increased reactivity to negative emotional youths with severe mood dysregulation had a community
stimuli that is manifest verbally or behaviorally. For diagnosis of bipolar disorder at the time of recruitment.
example, the child responds to frustration with extended
temper tantrums (inappropriate for age and/or Not surprisingly, 84.9% of the youths in the severe mood
precipitating event), verbal rages, and/or aggression dysregulation sample met DSM-IV criteria for lifetime
toward people or property. Such events occur, on oppositional defiant disorder, while 86.3% met criteria for
average, at least three times a week.
lifetime ADHD. It is also notable that 58.2% met criteria
5. The symptoms in 2, 3, and 4 are currently present and for a lifetime anxiety disorder and 16.4% for lifetime major
have been present for at least 12 months without any
symptom-free periods exceeding 2 months. depressive disorder, although youths are not included in
the severe mood dysregulation sample if their irritability
6. The symptoms are severely impairing in at least one
setting (home, school, or with peers) and are at least can be attributed solely to a major depressive episode or
mildly impairing in a second setting. an anxiety disorder. These data indicate that the severe
mood dysregulation syndrome might be conceptualized
Exclusion criteria as a disruptive behavior disorder that includes significant
mood and anxiety symptoms.
1. Exhibits any of these cardinal manic symptoms:
s Elevated or expansive mood To more clearly place the severe mood dysregulation
s Grandiosity or inflated self-esteem phenotype within the context of DSM-IV, post hoc anal-
s Episodically decreased need for sleep
yses were performed using data from the NIMH Diag-
2. The symptoms occur in distinct periods lasting more nostic Interview Schedule for Children, Version IV (28),
than 1 day.
obtained from parents of youths in four community sam-
3. Meets criteria for schizophrenia, schizoaffective disorder, ples (approximately 9,600 youths) and two clinical sam-
pervasive developmental disorder, or posttraumatic
ples (approximately 2,100 youths). A proxy for the severe
stress disorder.
mood dysregulation diagnosis required three symptoms
4. Meets criteria for substance abuse disorder in the past 3
of oppositional defiant disorder: temper tantrums, being
months.
angry or resentful (each at least “a few days a week”), and
5. IQ <70.
being touchy or easily annoyed (nearly every day). In the
6. The symptoms are due to the direct physiological effects community samples, 15% of youths with oppositional
of a drug of abuse, or to a general medical or
defiant disorder met criteria for the severe mood dysregu-
neurological condition.
lation proxy; in clinical samples, the severe mood dysregu-
a
Adapted from Leibenluft et al. (14). lation phenotype accounted for approximately a quarter
of the youths with oppositional defiant disorder (P. Fisher,
J.B.Turner, unpublished 2010 data).
or even brief manic or hypomanic episodes (i.e., ≥1 day)
are excluded from the severe mood dysregulation group.
Longitudinal Studies
While most children with irritability experience fluctua-
tions in the frequency and intensity of their symptoms, Longitudinal data provide a particularly important
this in and of itself does not constitute a manic or hypo- approach to evaluating the validity of classification in
manic episode unless the intensification of the irritability pediatric psychopathology. Two pediatric syndromes
is accompanied by the onset or worsening of the DSM-IV can be viewed as pathophysiologically similar when they
criterion B symptoms of mania. exhibit a similar course and predict similar risks for an
Since 2002, 146 youths with severe mood dysregulation adult phenotype, such as classic adult bipolar disorder,
have been studied at NIMH (Table 1). To make the diag- where considerable data exist on the validity of the adult
nosis of severe mood dysregulation, we use a module that phenotype. Thus, in assessing whether severe mood dys-
is appended to the Schedule for Affective Disorders and regulation is a developmental manifestation of mania, a

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 ELLEN LEIBENLUFT

crucial question is whether youths with the syndrome, TABLE 1. Demographic and Clinical Characteristics of
Youths With Severe Mood Dysregulation Studied at NIMH
when followed through adolescence and into adulthood,
Since 2002
develop manic episodes, hypomanic episodes, or bipolar
Characteristica
disorder not otherwise specified.
Relevant longitudinal data have been collected in both Mean SD
clinical and community samples. In our clinical research Age at study entry (years) 11.7 2.5
Age at illness onset (years) (N=71) 4.9 2.0
sample, we assessed rates of mood episodes in 84 youths
IQ (N=108) 103.3 13.1
with severe mood dysregulation and 93 youths with DSM-
Children’s Global Assessment Score at 45.8 6.9
IV bipolar disorder over a median of 28.4 months (21). study entry (N=140)
Only one patient (1.2%) with severe mood dysregulation, Number of DSM-IV diagnoses 2.9 1.2
but 58 (62.4%) with bipolar disorder, exhibited at least one Number of medications at study entry 2.1 1.6
new manic, hypomanic, or mixed episode during follow- N %
up (Mann-Whitney U=2,720, z=–3.48, p<0.001). Thus, in On medication at study entry 111 76.0
Male 96 65.8
this clinical sample, rates of prospectively observed manic
Lifetime history of
episodes were 50 times higher in bipolar disorder than
Attention deficit hyperactivity disorder 126 86.3
in severe mood dysregulation. Longer studies with larger (ADHD)
clinical samples are needed. Oppositional defiant disorder 124 84.9
Post hoc analyses of large community samples that have ADHD and oppositional defiant disorder 110 75.3
been followed for as long as 20 years complement the clin- Anxiety disorderb 85 58.2
ical data. None of these studies was designed to address Major depressive disorder 24 16.4
specific questions regarding the outcome of irritability. Conduct disorder 7 4.8
History of psychiatric hospitalization 55 37.7
Using post hoc proxy criteria for severe mood dysregula- a
N=146 unless otherwise indicated.
tion, Brotman et al. (29) found that compared to youths b
Includes separation anxiety disorder, generalized anxiety disorder,
who never met these criteria, those who met them at a and social phobia.
mean age of 10.6 years (SD=1.4) were seven times more
likely to meet criteria for a unipolar depressive disorder
at a mean age of 18.3 years (SD=2.1) (odds ratio=7.2, 95% sitionality, not irritability, and in including patients with
confidence interval [CI]=1.3–38.8, p=0.02). The lifetime less severe illness. Studies indicate that the longitudinal
prevalence of severe mood dysregulation in this sample predictions of oppositional defiant disorder are protean,
(N=1,420, ages 9–19 years) was 3.3%, whereas only 0.1% of including unipolar depressive and anxiety disorders
the sample met criteria for bipolar disorder. Thus, unlike (32–35) and, in some instances, bipolar disorder (33, 34).
the above-noted clinic-based study, which explicitly In particular, data indicate that the irritable, but not the
recruited children with bipolar disorder, this epidemio- oppositional, dimension of oppositional defiant disorder
logic study had relatively limited power to compare severe may be associated specifically with mood and anxiety dis-
mood dysregulation and bipolar disorder, since bipolar orders (36–38). The decomposition of oppositional defiant
disorder is far rarer than severe mood dysregulation in the disorder into its component parts, including a continued
community. focus on the specific predictions of irritability, might
In another community study, Stringaris et al. (30) improve the prognostic power of this common clinical
reported on 631 individuals followed from a mean age of presentation in youths.
13.8 years (SD=2.6) to a mean age of 33.2 years (SD=2.9),
beyond the peak age of risk for bipolar disorder. Chronic
irritability in adolescence predicted major depressive
Family History/Heritability
disorder at age 33 (odds ratio=1.33, 95% CI=1.00–1.78, If severe mood dysregulation is a developmental pheno-
p<0.05) as well as generalized anxiety disorder (odds type of bipolar disorder, one would expect children with
ratio=1.72, 95% CI=1.04–2.87, p<0.05) and dysthymia severe mood dysregulation to be as likely as those with
(odds ratio=1.81, 95% CI=1.06–3.12, p<0.01). The study bipolar disorder to have a parent with bipolar disorder. To
had a sufficient number of participants with bipolar dis- test this hypothesis, one small study (39) compared paren-
order to examine predictors of the illness (31), and ado- tal diagnoses (determined by clinicians blind to children’s
lescent irritability was not one of them. Thus, although diagnoses) in samples of youths with severe mood dys-
Brotman et al. (29) and Stringaris et al. (30) used different regulation or bipolar disorder. The two samples differed in
methods, both studies found that adolescent irritability the prevalence of parental bipolar disorder: 33.3% in the
predicted adult unipolar depressive and anxiety disorders. pediatric bipolar disorder sample compared with 2.7% in
To a certain extent, these findings are consistent with the severe mood dysregulation sample (odds ratio=18.0,
studies of youths with oppositional defiant disorder. As 95% CI=1.9–171, p≤0.01); the latter prevalence is similar
noted above, oppositional defiant disorder differs from to what might be expected in a community sample. Like
severe mood dysregulation in focusing primarily on oppo- the longitudinal data, these family-based data suggest that

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SEVERE MOOD DYSREGULATION, IRRITABILITY, AND BIPOLAR DISORDER IN YOUTHS

severe mood dysregulation is not a developmental pheno- In the first two domains, data also indicate that despite
type of bipolar disorder. Limitations of the study included similar behavioral deficits in the two patient groups, the
small sample size and ascertainment bias. mediating neural circuitry differs. These findings are con-
While the results of this preliminary family study sug- sistent with other work suggesting that neuroimaging
gest a differentiation between severe mood dysregulation techniques may be more sensitive than behavioral para-
and bipolar disorder, they do not address the familiality of digms in detecting between-group differences (53, 54).
severe mood dysregulation itself, which was not assessed From a systems neuroscience perspective, irritability
in parents (39). In addition, while other studies have may result from an inability to engage top-down mecha-
examined family members of children with bipolar dis- nisms (i.e., selective attention or higher-order mental
order, none of them contrasted diagnoses in the families processes [55]) in order to inhibit maladaptive responses
of children with classically defined bipolar disorder with occurring in the setting of frustration, where frustra-
diagnoses in the families of children with nonepisodic, tion is conceptualized as the emotional response that
severe, chronic irritability (40, 41). Indeed, no published occurs when goal attainment is blocked. The face emo-
work has addressed the familiality or heritability of severe tion labeling, response reversal, and attentional deficits
mood dysregulation or irritability, but several publications observed in severe mood dysregulation, combined with
have focused on related constructs. For example, studies recent research on emotion regulation in healthy volun-
indicate that oppositional defiant disorder and aggres- teers and in patients with affective aggression, suggest a
sion are subject to genetic influences (42–47). In addition, testable pathophysiologic model for irritability in youths
a phenotype based on scores in the clinical range of the (Figure 2).
attention, aggression, and anxious/depressed subscales The ability to accurately process social cues, which is a
of the Child Behavior Checklist (that is, the Child Behav- core social-emotional function that facilitates both emo-
ior Checklist–juvenile bipolar disorder profile) appears to tion regulation and social competence (55), appears to be
be heritable (48, 49). Although this profile was originally deficient in both severe mood dysregulation and pediatric
described as associated with the diagnosis of pediatric bipolar disorder (56, 57). Deficits in face emotion label-
bipolar disorder, data are mixed on that point, and some ing are not simply nonspecific correlates of childhood
data suggest that the profile might be more akin to severe psychopathology; Guyer et al. (56) found deficits relative
mood dysregulation than to episodic bipolar disorder (11, to healthy comparison subjects in patients with bipolar
12, 50–52). In sum, it appears that irritability, character- disorder and severe mood dysregulation but not in youths
ized by outbursts and inter-outburst negative mood, may with ADHD and/or conduct disorder, or in those with anx-
be significantly influenced by genetic factors. iety disorders and/or major depressive disorder (Figure
3). The fact that only the severe mood dysregulation and
bipolar disorder groups differed from the healthy com-
Pathophysiology parison group in performance on a face emotion iden-
In psychiatric nosology, pathophysiology is an impor- tification task suggests that severe mood dysregulation
tant but as yet elusive validator. A major goal of current and bipolar disorder might share some pathophysiologic
psychiatric research is to identify biomarkers to guide mechanisms.
diagnosis and treatment. Extending this approach, emerg- However, examinations of the neural circuitry engaged
ing research aims to identify neural mechanisms differen- in each group during face emotion labeling highlight the
tiating not only patients of one phenotype from healthy fact that similar behavioral deficits can result from mul-
individuals but also patients of two phenotypes from each tiple forms of circuitry dysfunction. fMRI data suggest that
other and from healthy individuals (53). In that vein, the despite similar face emotion labeling deficits in severe
first pathophysiologic studies of severe mood dysregula- mood dysregulation and bipolar disorder, neural activity
tion were designed to provide “proof of principle” that, in the amygdala differs between these two groups. Youths
using behavioral and biological measures obtained in the with severe mood dysregulation exhibited lower amygdala
laboratory and with functional MRI (fMRI), severe mood activity while rating their subjective fear versus nose width
dysregulation and bipolar disorder could be differentiated of neutral faces, relative to patients with bipolar disorder,
from each other and from healthy individuals. Much like nonirritable youths with ADHD, and healthy comparison
the family studies, studies in this area need to contrast subjects (58) (Figure 4). The finding of decreased amyg-
children with classically defined bipolar disorder and chil- dala activity in severe mood dysregulation during face
dren with other phenotypes, such as chronic irritability. emotion processing is similar to one reported earlier in
As described below, behavioral data from these studies youths with major depressive disorder (53); the similarity
indicate that both youths with severe mood dysregulation is notable given longitudinal associations between severe
and those with bipolar disorder differ from healthy com- mood dysregulation or chronic irritability and depressive
parison subjects in face emotion labeling ability, degree of disorders (29, 30).
subjective distress reported while performing a frustrating Another of the core abilities for social-emotional
task, and performance on response reversal paradigms. behavior suggested by Ochsner (55) is “context-sensitive

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 ELLEN LEIBENLUFT

FIGURE 2. Psychological Processes and Neural Circuits Hypothesized to Contribute to Pathologic Irritabilitya

Amplification
of Frustration

Dysregulated
attention-emotion
interactions

Decreased s !MYGDALA
Threshold s !##
s $ORSAL 0&#
s 6ENTRAL 0&#
s 0ARIETAL #ORTEX

Misinterpretation
of emotional
stimuli

s !MYGDALA
s 4EMPORAL #ORTEX
Goal s -EDIAL 0&# Increased irritability
&RUSTRATION
attainment blocked Behavioral dyscontrol

Decreased
CONTEXT SENSITIVE
Increased regulation
Probability
s !##
s #AUDATE
s .!CC
s -EDIAL 0&#
s 6ENTRAL 0&#

a
ACC=anterior cingulate cortex; PFC=prefrontal cortex; NAcc=nucleus accumbens.

regulation,” or the ability to adapt one’s behavior to chang- a complementary hypothesis is that the response of irri-
ing environmental contingencies. Such regulation can table individuals to frustrating contexts differs from that
be assessed using response reversal paradigms, in which of healthy comparison subjects. If the goal is to elucidate
participants must adapt their responses to changing mechanisms mediating irritable outbursts in youths, one
stimulus-reward associations. As suggested by Blair (59), research strategy involves neuroimaging while partici-
an individual with deficiencies in response reversal would pants complete frustrating tasks. A study using a rigged
be at high risk of encountering frustrating situations and task to elicit frustration found that while youths with severe
thus of exhibiting irritable or aggressive behavior. In this mood dysregulation and those with bipolar disorder both
way, response reversal deficits may play a causal role in reported more frustration than did healthy comparison
the irritability characteristic of severe mood dysregula- subjects, event-related-potential measures differentiated
tion. Patients with bipolar disorder and those with severe the two groups. Youths with bipolar disorder had deficient
mood dysregulation both differ from healthy comparison top-down executive attention (i.e., decreased parietal P3
subjects in performance on response reversal paradigms waves) specifically during frustration, while youths with
(60, 61). Ongoing research will test whether the neural severe mood dysregulation had deficits in bottom-up early
circuitry mediating such deficits in severe mood dysregu- attentional processes (i.e., decreased parietal, temporal,
lation and bipolar disorder differs between these patient and central N1 and P1 waves) during both frustrating and
groups, as it did in the case of face emotion labeling. This nonfrustrating blocks (63). Ongoing studies are extending
fMRI work will use a response reversal paradigm that has this work using magnetoencephalography and fMRI (64).
already been used in youths with ADHD or psychopathic The finding of early attentional deficits in severe mood
traits, thus also allowing for comparisons with these dysregulation is similar to results reported in youths with
patient groups (62). ADHD (65). Indeed, since the criteria for severe mood dys-
While response reversal deficits may increase an indi- regulation require the presence of three symptoms that
vidual’s likelihood of encountering frustrating situations, overlap between ADHD and the criterion B symptoms

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SEVERE MOOD DYSREGULATION, IRRITABILITY, AND BIPOLAR DISORDER IN YOUTHS

FIGURE 3. Face Emotion Labeling Errors, Adjusted for Sex, FIGURE 4. Left Amygdala Activation During Ratings of Sub-
Age, IQ, and Ethnicity, in Youths With Mood and Behavior jective Fear Versus Nose Width While Viewing Neutral Facesa
Disordersa

Bipolar Disorder ADHD/CD

2.0 Severe Mood ANX/MDD
Dysregulation
HC

1.6
Number of Errors

1.2
8

6
0.8
4

2
0.4
0

0 0.0010
Happy Sad Fearful Angry
Emotion 0.0008
a
Adapted from Guyer et al. (56). Bipolar disorder (N=42); severe
mood dysregulation (N=39); ANX/MDD=generalized anxiety, so- 0.0006
cial phobia, separation anxiety, and/or major depression (N=44); Mean (±SE)
ADHD/CD=attention deficit hyperactivity disorder and/or con- 0.0004
duct disorder (N=35); HC=healthy comparison subjects (N=92).
Between-group differences: severe mood dysregulation > ANX/ 0.0002
MDD, ADHD/CD, p<0.01; bipolar disorder > ANX/MDD, ADHD/CD,
p<0.001; severe mood dysregulation and bipolar disorder did not 0
differ.
–0.0002

–0.0004

for mania, it is not surprising that 86.3% of our severe –0.0006

mood dysregulation sample met criteria for ADHD (Table Healthy ADHD Bipolar Severe Mood
Comparison (N=18) Disorder Dysregulation
1). The neurobiology of emotional dysfunction in ADHD (N=37) (N=43) (N=29)
has received relatively little research attention, although
b c d
interest is growing (66–68). Data indicate differences in
amygdala activity in nonirritable youths with ADHD rela- e
tive to those with severe mood dysregulation, those with f
a
bipolar disorder, and healthy comparison subjects during Reprinted from Brotman et al. (58).
b
Amygdala activation in ADHD patients was greater than that for
face processing (58), and considerable research has found healthy comparison subjects (p=0.05).
high comorbidity between oppositional defiant disorder c
Amygdala activation in ADHD patients was greater than that
and ADHD (33). Thus, emotional dysregulation in ADHD for bipolar disorder patients (p=0.05).
d
Amygdala activation in severe mood dysregulation patients was
merits significantly more study. less than that for bipolar disorder patients (p=0.04).
Conversely, few data have been generated to character- e
Amygdala activation in severe mood dysregulation patients was
ize the nature of attentional dysregulation in severe mood less than that for ADHD patients (p<0.01).
f
Amygdala activation in severe mood dysregulation patients was
dysregulation, particularly in emotional contexts, so that less than that for healthy comparison subjects (p=0.04).
too is an important area for future research. Behavioral
and event-related-potential data suggest that youths with
severe mood dysregulation, compared to those with bipo-
lar disorder and/or healthy comparison subjects, may with severe mood dysregulation, and the precise nature of
have reduced attentional interference from emotional that abnormality, is important because such interactions
distracters (63, 68a). However, contradicting these find- may play a central role in emotion regulation (69, 70).
ings are data from youths with severe mood dysregulation Of course, irritability occurs in the context of many dif-
who had increased amygdala activation relative to other ferent clinical presentations (e.g., chronically in severe
groups when asked to focus on nose width rather than on mood dysregulation; during episodes of mania or depres-
the emotional expression of a face, suggesting that youths sion in bipolar disorder; and in specific contexts in anxious
with severe mood dysregulation may have difficulty focus- children and individuals with posttraumatic stress disor-
ing away from face emotions (58). The extent to which der), and data suggest that the pathophysiology of irritabil-
emotion-attention interactions are abnormal in youths ity, including the specific nature of the attentional control

136 ajp.psychiatryonline.org Am J Psychiatry 168:2, February 2011

 ELLEN LEIBENLUFT

deficits, will vary across clinical presentations. In some sizes of 0.69 and 0.84 for stimulants in the treatment of
clinical states, such as acute mania, bottom-up mecha- covert and overt aggression, respectively (86). A number of
nisms may be particularly important, since increased double-blind controlled trials demonstrate the efficacy of
arousal may be associated with increased irritability (71). SSRIs in treating irritability associated with premenstrual
The extent to which the model described in Figure 2 applies dysphoric disorder (87, 88), and one trial found that fluox-
in different clinical phenotypes is therefore an important etine was more effective than placebo in treating adults
area for future research. In addition, once the heritability with intermittent explosive disorder (89).
of irritability is established, genetic imaging studies can Clinicians or researchers who conceptualize severe,
explore associations between genotype and neural activity nonepisodic irritability as a phenotype of bipolar disorder
in the setting of frustration and other emotional contexts. are reluctant to treat youths with severe mood dysregula-
tion with stimulants or SSRIs because of concerns about
Treatment: Current Literature and precipitating mania. However, it is important to differ-
entiate activation from mania when assessing adverse
Research Gaps events secondary to SSRIs. Activation is common (present
The distinction between severe mood dysregulation and in some 10%–20% of youths receiving SSRIs) and gener-
bipolar disorder may have important treatment implica- ally responds to temporary discontinuation of medication
tions. If severe mood dysregulation is a pediatric bipo- with reinstitution at a lower dosage (90, 91). Mania in
lar disorder phenotype, then first-line treatment would response to SSRIs is uncommon and can be difficult to
include mood stabilizers and atypical antipsychotics, with differentiate from spontaneous cycling (92, 93); however,
stimulants and selective serotonin reuptake inhibitors there is evidence that children may be at higher risk than
(SSRIs) being relatively contraindicated (72). On the other adults for antidepressant-induced mania and/or activa-
hand, if severe mood dysregulation is more similar patho- tion (94, 95).
physiologically to unipolar depressive and anxiety disor- There are no systematic data regarding the risk of stim-
ders, as well as to ADHD, then stimulants and SSRIs would ulant-induced mania in severe mood dysregulation. How-
be recommended. Given the relatively high side effect ever, preliminary data suggest that youths with related
burden of atypical antipsychotics, coupled with the risks phenotypes may respond as well to stimulants as those
of using antidepressants or stimulants in bipolar disorder, with uncomplicated ADHD (96, 97). Considerably more
this differentiation is important (73). Indirect evidence sug- research is needed to determine whether treatment with
gests that many youths with severe mood dysregulation are SSRIs and/or stimulants is effective and safe in treat-
receiving treatment with atypical antipsychotics, particu- ing severe mood dysregulation. A particularly important
larly risperidone (74–77). Possible contributors to this trend question is whether children with the severe mood dys-
are that risperidone has received a Food and Drug Adminis- regulation phenotype and a parent with bipolar disorder
tration indication for irritability (specifically, in autism [78]) differ from those with severe mood dysregulation but no
and that some controlled studies support its use in aggres- family history of bipolar disorder in their risk of develop-
sive children with disruptive behavior disorders (79). ing mania, either spontaneously or in response to an acti-
The only treatment trial of severe mood dysregulation vating medication.
is a small, negative trial of lithium (80); earlier studies In both medication and psychotherapeutic treatment
showed lithium to be effective in treating aggression in the trials, irritability is rarely the major outcome variable.
setting of conduct disorder (81, 82). A recent controlled Few scales capture the phenomenology of irritability pre-
trial of youths with a phenotype similar to severe mood cisely, and those that do tend to focus on its more extreme
dysregulation (ADHD and aggression unresponsive to behavioral manifestations, such as aggression (for exam-
stimulants) found divalproex combined with behavioral ple, see references 78 and 83). While some psychothera-
therapy to be more effective than stimulant plus placebo peutic trials focus on overt aggression in adolescents, few
and behavior therapy (83). That study built on previous trials have examined school-age children with frequent
trials of divalproex in the treatment of irritable or aggres- outbursts that are impairing but not always violent (98,
sive youths (84, 85). 99). Furthermore, such trials frequently include youths
A second treatment trial of severe mood dysregulation with both proactive and reactive aggression, whereas
is under way (clinicaltrials.gov identifier NCT00794040) most youths with severe mood dysregulation exhibit only
to compare a stimulant plus citalopram to a stimulant the latter. Since psychotherapeutic interventions are likely
plus placebo. The study builds on the longitudinal data to play an essential role in the treatment of severe mood
reviewed above suggesting that severe mood dysregula- dysregulation, high-priority areas for research include the
tion is on a pathophysiologic continuum with unipolar development of more fine-grained assessment tools for
depressive and anxiety disorders, as well as data suggest- irritability, as well as interventions aimed at a range of its
ing that both stimulants and SSRIs might be effective in manifestations. Several interventions designed for chil-
treating irritability and/or aggression. For example, a dren with severe mood disorders, including bipolar disor-
meta-analysis of stimulant trials in ADHD found effect der, may include relevant components (100, 101).

Am J Psychiatry 168:2, February 2011 ajp.psychiatryonline.org 137

SEVERE MOOD DYSREGULATION, IRRITABILITY, AND BIPOLAR DISORDER IN YOUTHS

Future Directions in Nosology: DSM-5 indicating that the severe mood dysregulation/temper
dysregulation disorder with dysphoria phenotype is on a
One important positive outcome of the controversy phenomenological continuum with oppositional defiant
about pediatric bipolar disorder is the attention drawn to disorder. At the time of this writing, DSM-5 has not been
a relatively large population of severely impaired youths finalized, and final decisions will be informed by field tri-
who do not fit well into any one DSM-IV category. In als and further discussion.
DSM-IV, the severe mood dysregulation phenotype is
best captured by oppositional defiant disorder. However,
oppositional defiant disorder captures a broad range of
Conclusions
severity (whereas youths with severe mood dysregula- At least two important lessons can be drawn from the
tion are all, by definition, severely impaired) and focuses controversy about the diagnosis of pediatric bipolar disor-
strongly on oppositional behavior, which may have differ- der. First, available data do not support categorizing chil-
ent treatment implications and longitudinal predictions dren with nonepisodic severe irritability as manic. That is,
than irritability (36, 37). evidence suggests that youths with nonepisodic irritability
Thus, in considering how to better serve the clinical 1) are at increased risk for unipolar depressive and anxiety
needs of youths with the severe mood dysregulation phe- disorders, rather than manic episodes, as they age; 2) do
notype, the DSM-5 work groups considered creating a not have high familial rates of bipolar disorder; and 3) dif-
specifier for oppositional defiant disorder that focused on fer pathophysiologically from youths with DSM-IV bipo-
the irritable, rather than the headstrong, criteria for the dis- lar disorder. Thus, at this time, the available data support
order; required impairment in at least two of three settings reserving the diagnosis of mania for youths who have a
(at home, at school, and with peers); and set a high thresh- distinct change in mood (elevated, expansive, or irritable)
old for number of outbursts per week. Alternatively, the accompanied by the onset or worsening of the criterion B
work groups considered creating a separate diagnosis to symptoms of mania. This conclusion is tempered by the
encompass the severe mood dysregulation phenotype. The fact that the research requires replication by other groups
latter strategy was adopted in the draft proposal for DSM-5, and in larger samples. Also, it is possible that as the genetics
which thus includes the diagnosis of temper dysregulation and pathophysiology of both bipolar disorder and severe
disorder with dysphoria (102). The criteria for this diagno- nonepisodic irritability are discovered, these two clinical
sis resemble those for severe mood dysregulation, with the phenotypes will be found to share pathogenic mechanisms
major difference being that temper dysregulation disorder and thus may ultimately be considered to be on a patho-
with dysphoria does not require “hyperarousal”—that is, physiologic spectrum with each other as well as with major
the criterion B symptoms for mania and the ADHD crite- depressive disorder. It is also important to note that the
ria (Figure 1, inclusion criterion 3). In the judgment of the longitudinal outcome of children with a family history of
DSM work groups, the presence of such symptoms would bipolar disorder and nonepisodic irritability is unknown.
best be denoted by assigning the diagnoses of both tem- The second lesson is that irritability is a common, yet
per dysregulation disorder with dysphoria and ADHD to relatively understudied, symptom in pediatric psycho-
patients who meet criteria for both syndromes. However, a pathology. Children with DSM-IV bipolar disorder and
disadvantage of this decision is that temper dysregulation those with severe mood dysregulation are both severely
disorder with dysphoria itself has not been studied system- (and equally) impaired, and data suggest that the severe
atically. As with severe mood dysregulation, the criteria for mood dysregulation phenotype is considerably more
temper dysregulation disorder require pervasive negative- common than bipolar disorder (29). Consequently, there
valence mood between outbursts. is a pressing need for controlled treatment trials in severe
The work groups’ decision to propose a separate diag- mood dysregulation or related phenotypes. While a few
nosis of temper dysregulation disorder with dysphoria have been conducted (for example, see references 80 and
rather than an oppositional defiant disorder specifier was 83), the small number of pharmacologic or psychosocial
based on several considerations. Among the advantages of intervention trials pales in comparison with the clinical
the new diagnosis are that it would be placed in the mood, need. In particular, an open and important question is
rather than the disruptive behavior, section of DSM-5, whether the first-line treatment for severe mood dysreg-
thus highlighting the fact that irritability is a mood distur- ulation should be the same as for bipolar disorder. Such
bance, frequently accompanied by anxiety, that predicts clinical trials would be facilitated by the further refine-
subsequent mood and anxiety disorders (29, 30, 36, 37). ment of scales that measure the multiple manifestations
The goal would be to draw clinicians’ attention to inter- of irritability and are sensitive to change. Other important
ventions targeting mood and anxiety disorders and to research gaps include the continuity between severe irrita-
encourage researchers to undertake both pharmacologic bility in youth and adult phenotypes, including intermit-
and psychotherapeutic clinical trials for this underserved tent explosive disorder (89); the heritability and genetics
yet severely impaired population. The major argument for of irritability; and the mediating neural circuitry. As noted
a specifier is that it would be more consistent with data above, irritability can be conceptualized within the frame-

138 ajp.psychiatryonline.org Am J Psychiatry 168:2, February 2011

 ELLEN LEIBENLUFT

work of affective neuroscience and studied with fMRI and 12. Volk HE, Todd RD: Does the Child Behavior Checklist juvenile
bipolar disorder phenotype identify bipolar disorder? Biol Psy-
other techniques.
chiatry 2007; 62:115–120
Irritability is a pressing problem for clinical neurosci- 13. Rucklidge JJ: Retrospective parent report of psychiatric his-
ence and treatment research. Indeed, given the number of tories: do checklists reveal specific prodromal indicators for
affected children and the severity of their impairment, the postpubertal-onset pediatric bipolar disorder? Bipolar Disord
need could not be greater. 2008; 10:56–66
14. Leibenluft E, Charney DS, Towbin KE, Bhangoo RK, Pine DS:
Defining clinical phenotypes of juvenile mania. Am J Psychia-
Received May 26, 2010; revision received Sept. 21, 2010; accepted try 2003; 160:430–437
Sept. 27, 2010 (doi: 10.1176/appi.ajp.2010.10050766). From the 15. Galanter CA, Leibenluft E: Frontiers between attention deficit
Section on Bipolar Spectrum Disorders, Emotion and Development hyperactivity disorder and bipolar disorder. Child Adolesc Psy-
Branch, NIMH. Address correspondence to Dr. Leibenluft, Section on chiatr Clin N Am 2008;17:325–346
Bipolar Spectrum Disorders, NIMH, Bldg. 15K, MSC-2670, Bethesda, 16. Still GF: Some abnormal psychical conditions in children: ex-
MD 20892-2670; [email protected] (e-mail).
cerpts from three lectures. J Atten Disord 2006; 10:126–136
Dr. Leibenluft reports no financial relationships with commercial
17. Barkley RA: Behavioral inhibition, sustained attention, and
interests.
Supported by the NIMH Intramural Research Program. executive functions: constructing a unifying theory of ADHD.
The author thanks Melissa A. Brotman, Ph.D., Megan Connolly, Psychol Bull 1997; 121:65–94
B.A., and Caroline Haimm, B.A., for assistance with manuscript prep- 18. Costello EJ, Foley DL, Angold A: 10-year research update re-
aration. She also thanks Daniel S. Pine, M.D., and Kenneth E. Towbin, view: the epidemiology of child and adolescent psychiatric
M.D., past and present staff of the Section on Bipolar Spectrum Dis- disorders, II: developmental epidemiology. J Am Acad Child
orders, and our patients and their families for their contributions to Adolesc Psychiatry 2006; 45:8–25
the research described here. 19. Birmaher B, Axelson D, Strober M, Gill MK, Valeri S, Chiap-
petta L, Ryan N, Leonard H, Hunt J, Iyengar S, Keller M: Clini-
cal course of children and adolescents with bipolar spectrum
References disorders. Arch Gen Psychiatry 2006; 63:175–183
1. Blader JC, Carlson GA: Increased rates of bipolar disorder di- 20. DelBello MP, Hanseman D, Adler CM, Fleck DE, Strakowski SM:
agnoses among US child, adolescent, and adult inpatients, Twelve-month outcome of adolescents with bipolar disorder
1996–2004. Biol Psychiatry 2007; 62:107–114 following first hospitalization for a manic or mixed episode.
2. Moreno C, Laje G, Blanco C, Jiang H, Schmidt AB, Olfson M: Am J Psychiatry 2007; 164:582–590
National trends in the outpatient diagnosis and treatment of 21. Stringaris A, Baroni A, Haimm C, Brotman M, Lowe CH, My-
bipolar disorder in youth. Arch Gen Psychiatry 2007; 64:1032– ers F, Rustgi E, Wheeler W, Kayser R, Towbin K, Leibenluft E:
1039 Pediatric bipolar disorder versus severe mood dysregulation:
3. Leibenluft E: Pediatric bipolar disorder comes of age. Arch Gen risk for manic episodes on follow-up. J Am Acad Child Adolesc
Psychiatry 2008; 65:1122–1124 Psychiatry 2010; 49:397–405
4. Biederman J, Klein RG, Pine DS, Klein DF: Resolved: mania is 22. Hyman SE: Can neuroscience be integrated into the DSM-V?
mistaken for ADHD in prepubertal children. J Am Acad Child Nat Rev Neurosci 2007; 8:725–732
Adolesc Psychiatry 1998; 37:1091–1099 23. Vitiello B, Stoff DM: Subtypes of aggression and their relevance
5. Biederman J, Faraone SV, Wozniak J, Mick E, Kwon A, Aleardi to child psychiatry. J Am Acad Child Adolesc Psychiatry 1997;
M: Further evidence of unique developmental phenotypic 36:307–315
correlates of pediatric bipolar disorder: findings from a large 24. Marshburn EC, Aman MG: Factor validity and norms for the ab-
sample of clinically referred preadolescent children assessed errant behavior checklist in a community sample of children
over the last 7 years. J Affect Disord 2004; 82(suppl):S45–S58 with mental retardation. J Autism Dev Disord 1992; 22:357–
6. Mick E, Spencer T, Wozniak J, Biederman J: Heterogeneity 373
of irritability in attention-deficit/hyperactivity disorder sub- 25. Kolko DJ, Baumann BL, Bukstein OG, Brown EJ: Internalizing
jects with and without mood disorders. Biol Psychiatry 2005; symptoms and affective reactivity in relation to the severity of
58:576–582 aggression in clinically referred, behavior-disordered children.
7. Papolos D, Mattis S, Golshan S, Molay F: Fear of harm, a pos- J Child Fam Stud 2007; 16:745–759
sible phenotype of pediatric bipolar disorder: a dimensional 26. Axelson D, Birmaher B, Strober M, Gill MK, Valeri S, Chiap-
approach to diagnosis for genotyping psychiatric syndromes. J petta L, Ryan N, Leonard H, Hunt J, Iyengar S, Bridge J, Keller
Affect Disord 2009; 118:28–38 M: Phenomenology of children and adolescents with bipolar
8. Baroni A, Lunsford JR, Luckenbaugh DA, Towbin KE, Leiben- spectrum disorders. Arch Gen Psychiatry 2006; 63:1139–1148
luft E: Practitioner review: the assessment of bipolar disorder 27. Shaffer D, Gould MS, Brasic J, Ambrosini P, Fisher P, Bird H,
in children and adolescents. J Child Psychol Psychiatry 2009; Aluwahlia S: A Children’s Global Assessment Scale (CGAS). Arch
50:203–215 Gen Psychiatry 1983; 40:1228–1231
9. Geller B, Warner K, Williams M, Zimerman B: Prepubertal and 28. Shaffer D, Fisher P, Lucas CP, Dulcan MK, Schwab-Stone ME:
young adolescent bipolarity versus ADHD: assessment and va- NIMH Diagnostic Interview Schedule for Children, Version IV
lidity using the Wash-U-KSADS, CBCL, and TRF. J Affect Disord (NIMH DISC-IV): description, differences from previous ver-
1998; 51:93–100 sions, and reliability of some common diagnoses. J Am Acad
10. Geller B, Tillman R, Bolhofner K: Proposed definitions of bipo- Child Adolesc Psychiatry 2000; 39:28–38
lar I disorder episodes and daily rapid cycling phenomena in 29. Brotman MA, Schmajuk M, Rich BA, Dickstein DP, Guyer AE,
preschoolers, school-aged children, adolescents, and adults. J Costello EJ, Egger HL, Angold A, Pine DS, Leibenluft E: Prevalence,
Child Adolesc Psychopharmacol 2007; 17:217–222 clinical correlates, and longitudinal course of severe mood dys-
11. Faraone SV, Althoff RR, Hudziak JJ, Monuteaux M, Biederman J: regulation in children. Biol Psychiatry 2006; 60:991–997
The CBCL predicts DSM bipolar disorder in children: a receiver 30. Stringaris A, Cohen P, Pine DS, Leibenluft E: Adult outcomes
operating characteristic curve analysis. Bipolar Disord 2005; of youth irritability: a 20-year prospective community-based
7:518–524 study. Am J Psychiatry 2009; 166:1048–1054

Am J Psychiatry 168:2, February 2011 ajp.psychiatryonline.org 139

SEVERE MOOD DYSREGULATION, IRRITABILITY, AND BIPOLAR DISORDER IN YOUTHS

31. Johnson JG, Cohen P, Brook JS: Associations between bipolar Behavior Checklist-juvenile bipolar phenotype. Biol Psychiatry
disorder and other psychiatric disorders during adolescence 2006; 60:903–911
and early adulthood: a community-based longitudinal investi- 50. Biederman J, Petty CR, Monuteaux MC, Evans M, Parcell T, Fara-
gation. Am J Psychiatry 2000; 157:1679–1681 one SV, Wozniak J: The Child Behavior Checklist-pediatric bipo-
32. Copeland WE, Shanahan L, Costello EJ, Angold A: Childhood lar disorder profile predicts a subsequent diagnosis of bipolar
and adolescent psychiatric disorders as predictors of young disorder and associated impairments in ADHD youth growing
adult disorders. Arch Gen Psychiatry 2009; 66:764–772 up: a longitudinal analysis. J Clin Psychiatry 2009; 70:732–740
33. Nock MK, Kazdin AE, Hiripi E, Kessler RC: Lifetime prevalence, 51. McGough JJ, Loo SK, McCracken JT, Dang J, Clark S, Nelson SF,
correlates, and persistence of oppositional defiant disorder: Smalley SL: CBCL pediatric bipolar disorder profile and ADHD:
results from the National Comorbidity Survey Replication. J comorbidity and quantitative trait loci analysis. J Am Acad
Child Psychol Psychiatry 2007; 48:703–713 Child Adolesc Psychiatry 2008; 47:1151–1157
34. Kim-Cohen J, Caspi A, Moffitt TE, Harrington H, Milne BJ, Poul- 52. Diler RS, Birmaher B, Axelson D, Goldstein B, Gill M, Strober
ton R: Prior juvenile diagnoses in adults with mental disorder: M, Kolko DJ, Goldstein TR, Hunt J, Yang M, Ryan ND, Iyengar
developmental follow-back of a prospective-longitudinal co- S, Dahl RE, Dorn LD, Keller MB: The Child Behavior Checklist
hort. Arch Gen Psychiatry 2003; 60:709–717 (CBCL) and the CBCL-bipolar phenotype are not useful in diag-
35. Boylan K, Vaillancourt T, Boyle M, Szatmari P: Comorbidity of nosing pediatric bipolar disorder. J Child Adolesc Psychophar-
internalizing disorders in children with oppositional defiant macol 2009; 19:23–30
disorder. Eur Child Adolesc Psychiatry 2007; 16:484–494 53. Beesdo K, Lau JY, Guyer AE, McClure-Tone EB, Monk CS, Nelson
36. Stringaris A, Goodman R: Longitudinal outcome of youth op- EE, Fromm SJ, Goldwin MA, Wittchen HU, Leibenluft E, Ernst M,
positionality: irritable, headstrong, and hurtful behaviors have Pine DS: Common and distinct amygdala-function perturba-
distinctive predictions. J Am Acad Child Adolesc Psychiatry tions in depressed vs anxious adolescents. Arch Gen Psychiatry
2009; 48:404–412 2009; 66:275–285
37. Loeber R, Burke J, Pardini DA: Perspectives on oppositional de- 54. Poldrack RA: The role of fMRI in cognitive neuroscience: where
fiant disorder, conduct disorder, and psychopathic features. J do we stand? Curr Opin Neurobiol 2008; 18:223–227
Child Psychol Psychiatry 2009; 50:133–142 55. Ochsner KN: The social-emotional processing stream: five core
38. Stringaris A, Goodman R: Three dimensions of oppositionality constructs and their translational potential for schizophrenia
in youth. J Child Psychol Psychiatry 2009; 50:216–223 and beyond. Biol Psychiatry 2008; 64:48–61
39. Brotman MA, Kassem L, Reising MM, Guyer AE, Dickstein DP, 56. Guyer AE, McClure EB, Adler AD, Brotman MA, Rich BA, Kimes
Rich BA, Towbin KE, Pine DS, McMahon FJ, Leibenluft E: Pa- AS, Pine DS, Ernst M, Leibenluft E: Specificity of facial expres-
rental diagnoses in youth with narrow phenotype bipolar dis- sion labeling deficits in childhood psychopathology. J Child
order or severe mood dysregulation. Am J Psychiatry 2007; Psychol Psychiatry 2007; 48:863–871
164:1238–1241 57. Rich BA, Grimley ME, Schmajuk M, Blair KS, Blair RJR, Leiben-
40. Wozniak J, Faraone SV, Mick E, Monuteaux M, Coville A, Bie- luft E: Face emotion labeling deficits in children with bipolar
derman J: A controlled family study of children with DSM-IV disorder and severe mood dysregulation. Dev Psychopathol
bipolar I disorder and psychiatric co-morbidity. Psychol Med 2008; 20:529–546
2010; 40:1079–1088 58. Brotman MA, Rich BA, Guyer AE, Lunsford JR, Horsey SE, Reis-
41. Geller B, Tillman R, Bolhofner K, Zimerman B, Strauss NA, ing MM, Thomas LA, Fromm SJ, Towbin K, Pine DS, Leibenluft
Kaufmann P: Controlled, blindly rated, direct-interview family E: Amygdala activation during emotion processing of neutral
study of a prepubertal and early-adolescent bipolar I disorder faces in children with severe mood dysregulation versus ADHD
phenotype: morbid risk, age at onset, and comorbidity. Arch or bipolar disorder. Am J Psychiatry 2010; 167:61–69
Gen Psychiatry 2006; 63:1130–1138 59. Blair RJ: Psychopathy, frustration, and reactive aggression:
42. Burt SA: Rethinking environmental contributions to child and the role of ventromedial prefrontal cortex. Br J Psychol 2010;
adolescent psychopathology: a meta-analysis of shared envi- 101:383–399
ronmental influences. Psychol Bull 2009; 135:608–637 60. Dickstein DP, Nelson EE, McClure EB, Grimley ME, Knopf L,
43. Eley TC, Lichtenstein P, Stevenson J: Sex differences in the etiol- Brotman MA, Rich BA, Pine DS, Leibenluft E: Cognitive flexibil-
ogy of aggressive and nonaggressive antisocial behavior: re- ity in phenotypes of pediatric bipolar disorder. J Am Acad Child
sults from two twin studies. Child Dev 1999; 70:155–168 Adolesc Psychiatry 2007; 46:341–355
44. Seroczynski AD, Bergeman CS, Coccaro EF: Etiology of the im- 61. Dickstein DP, Finger EC, Brotman MA, Rich BA, Pine DS, Blair
pulsivity/aggression relationship: genes or environment? Psy- JR, Leibenluft E: Impaired probabilistic reversal learning in
chiatry Res 1999; 86:41–57 youths with mood and anxiety disorders. Psychol Med 2010;
45. Derks EM, Hudziak JJ, van Beijsterveldt CE, Dolan CV, Boomsma 40:1089–1100
DI: A study of genetic and environmental influences on mater- 62. Finger EC, Marsh AA, Mitchell DG, Reid ME, Sims C, Budhani S,
nal and paternal CBCL syndrome scores in a large sample of Kosson DS, Chen G, Towbin KE, Leibenluft E, Pine DS, Blair JR:
3-year-old Dutch twins. Behav Genet 2004; 34:571–583 Abnormal ventromedial prefrontal cortex function in children
46. Derks EM, Dolan CV, Hudziak JJ, Neale MC, Boomsma DI: As- with psychopathic traits during reversal learning. Arch Gen
sessment and etiology of attention deficit hyperactivity disor- Psychiatry 2008; 65:586–594
der and oppositional defiant disorder in boys and girls. Behav 63. Rich BA, Schmajuk M, Perez-Edgar KE, Fox NA, Pine DS, Leiben-
Genet 2007; 37:559–566 luft E: Different psychophysiological and behavioral responses
47. Hudziak JJ, Derks EM, Althoff RR, Copeland W, Boomsma DI: elicited by frustration in pediatric bipolar disorder and severe
The genetic and environmental contributions to oppositional mood dysregulation. Am J Psychiatry 2007; 164:309–317
defiant behavior: a multi-informant twin study. J Am Acad 64. Rich BA, Holroyd T, Carver FW, Onelio LM, Mendoza JK, Corn-
Child Adolesc Psychiatry 2005; 44:907–914 well BR, Fox NA, Pine DS, Coppola R, Leibenluft E: A pre-
48. Hudziak JJ, Althoff RR, Derks EM, Faraone SV, Boomsma DI: liminary study of the neural mechanisms of frustration in
Prevalence and genetic architecture of Child Behavior Check- pediatric bipolar disorder using magnetoencephalography.
list-juvenile bipolar disorder. Biol Psychiatry 2005; 58:562–568 Depress Anxiety 2010; 27:276–286
49. Althoff RR, Rettew DC, Faraone SV, Boomsma DI, Hudziak 65. Jonkman LM, Kemner C, Verbaten MN, Van Engeland H, Camf-
JJ: Latent class analysis shows strong heritability of the Child ferman G, Buitelaar JK, Koelega HS: Attentional capacity, a

140 ajp.psychiatryonline.org Am J Psychiatry 168:2, February 2011

 ELLEN LEIBENLUFT

probe ERP study: differences between children with attention- severe mood dysregulation. J Child Adolesc Psychopharmacol
deficit hyperactivity disorder and normal control children and 2009; 19:61–73
effects of methylphenidate. Psychophysiology 2000; 37:334– 81. Campbell M, Adams PB, Small AM, Kafantaris V, Silva RR, Shell J,
346 Perry R, Overall JE: Lithium in hospitalized aggressive children
66. Plessen KJ, Bansal R, Zhu H, Whiteman R, Amat J, Quackenbush with conduct disorder: a double-blind and placebo-controlled
GA, Martin L, Durkin K, Blair C, Royal J, Hugdahl K, Peterson BS: study. J Am Acad Child Adolesc Psychiatry 1995; 34:445–453
Hippocampus and amygdala morphology in attention-deficit/ 82. Malone RP, Delaney MA, Luebbert JF, Cater J, Campbell M: A
hyperactivity disorder. Arch Gen Psychiatry 2006; 63:795–807 double-blind placebo-controlled study of lithium in hospital-
67. Marsh AA, Finger EC, Mitchell DGV, Reid ME, Sims C, Kosson DS, ized aggressive children and adolescents with conduct disor-
Towbin KE, Leibenluft E, Pine DS, Blair RJR: Reduced amygdala der. Arch Gen Psychiatry 2000; 57:649–654
response to fearful expressions in children and adolescents 83. Blader JC, Schooler NR, Jensen PS, Pliszka SR, Kafantaris V: Ad-
with callous-unemotional traits and disruptive behavior disor- junctive divalproex versus placebo for children with ADHD and
ders. Am J Psychiatry 2008; 165:712–720 aggression refractory to stimulant monotherapy. Am J Psychia-
68. Volkow ND, Wang GJ, Kollins SH, Wigal TL, Newcorn JH, Telang try 2009; 166:1392–1401
F, Fowler JS, Zhu W, Logan J, Ma Y, Pradhan K, Wong C, Swan- 84. Donovan SJ, Stewart JW, Nunes EV, Quitkin FM, Parides M, Dan-
son JM: Evaluating dopamine reward pathway in ADHD: clini- iel W, Susser E, Klein DF: Divalproex treatment for youth with
cal implications. JAMA 2009; 302:1084–1091 explosive temper and mood lability: a double-blind, placebo-
68a. Rich BA, Brotman MA, Dickstein DP, Mitchell DG, Blair RJ, controlled crossover design. Am J Psychiatry 2000; 157:818–
Leibenluft E: Deficits in attention to emotional stimuli distin- 820; corrections, 157:1038, 157:1192
guish youth with severe mood dysregulation from youth with 85. Steiner H, Petersen ML, Saxena K, Ford S, Matthews Z: Di-
bipolar disorder. J Abnorm Child Psychol 2010; 38:695–706 valproex sodium for the treatment of conduct disorder: a
69. Posner MI, Rothbart MK: Attention, self-regulation, and con- randomized controlled clinical trial. J Clin Psychiatry 2003;
sciousness. Philos Trans R Soc Lond B Biol Sci 1998; 353:1915– 64:1183–1191
1927 86. Connor DF, Glatt SJ, Lopez ID, Jackson D, Melloni RH Jr: Psycho-
70. Mischel W, Shoda Y, Rodriguez MI: Delay of gratification in chil- pharmacology and aggression, I: a meta-analysis of stimulant
dren. Science 1989; 244:933–938 effects on overt/covert aggression-related behaviors in ADHD. J
71. Phillips ML, Ladouceur CD, Drevets WC: A neural model of vol- Am Acad Child Adolesc Psychiatry 2002; 41:253–261
untary and automatic emotion regulation: implications for un- 87. Halbreich U, O’Brien PM, Eriksson E, Backstrom T, Yonkers
derstanding the pathophysiology and neurodevelopment of KA, Freeman EW: Are there differential symptom profiles that
bipolar disorder. Mol Psychiatry 2008; 13:829, 833–857 improve in response to different pharmacological treatments
72. McClellan J, Kowatch R, Findling RL: Practice parameter for the of premenstrual syndrome/premenstrual dysphoric disorder?
assessment and treatment of children and adolescents with CNS Drugs 2006; 20:523–547
bipolar disorder. J Am Acad Child Adolesc Psychiatry 2007; 88. Landen M, Nissbrandt H, Allgulander C, Sorvik K, Ysander C, Er-
46:107–125 iksson E: Placebo-controlled trial comparing intermittent and
73. Correll CU, Manu P, Olshanskiy V, Napolitano B, Kane JM, Mal- continuous paroxetine in premenstrual dysphoric disorder.
hotra AK: Cardiometabolic risk of second-generation antipsy- Neuropsychopharmacology 2007; 32:153–161
chotic medications during first-time use in children and ado- 89. Coccaro EF, Lee RJ, Kavoussi RJ: A double-blind, randomized,
lescents. JAMA 2009; 302:1765–1773 placebo-controlled trial of fluoxetine in patients with intermit-
74. Weiss M, Panagiotopoulos C, Giles L, Gibbins C, Kuzeljevic B, tent explosive disorder. J Clin Psychiatry 2009; 70:653–662
Davidson J, Harrison, R: A naturalistic study of predictors and 90. Walkup J, Labellarte M: Complications of SSRI treatment. J Child
risks of atypical antipsychotic use in an attention-deficit/hyper- Adolesc Psychopharmacol 2001; 11:1–4
activity disorder clinic. J Child Adolesc Psychopharmacol 2009; 91. Reinblatt SP, DosReis S, Walkup JT, Riddle MA: Activation ad-
19:575–582 verse events induced by the selective serotonin reuptake in-
75. Olfson M, Blanco C, Liu L, Moreno C, Laje G: National trends hibitor fluvoxamine in children and adolescents. J Child Ado-
in the outpatient treatment of children and adolescents with lesc Psychopharmacol 2009; 19:119–126
antipsychotic drugs. Arch Gen Psychiatry 2006; 63:679–685 92. Gijsman HJ, Geddes JR, Rendell JM, Nolen WA, Goodwin GM: An-
76. Doey T, Handelman K, Seabrook JA, Steele M: Survey of atypi- tidepressants for bipolar depression: a systematic review of ran-
cal antipsychotic prescribing by Canadian child psychiatrists domized, controlled trials. Am J Psychiatry 2004; 161:1537–1547
and developmental pediatricians for patients aged under 18 93. Joseph MF, Youngstrom EA, Soares JC: Antidepressant-coinci-
years. Can J Psychiatry 2007; 52:363–368 dent mania in children and adolescents treated with selective
77. Carlson GA, Potegal M, Margulies D, Basile J, Gutkovich Z: Liq- serotonin reuptake inhibitors. Future Neurol 2009; 4:87–102
uid risperidone in the treatment of rages in psychiatrically 94. Martin A, Young C, Leckman JF, Mukonoweshuro C, Rosenheck
hospitalized children with possible bipolar disorder. Bipolar R, Leslie D: Age effects on antidepressant-induced manic con-
Disord 2010; 12:205–212 version. Arch Pediatr Adolesc Med 2004; 158:773–780
78. McCracken JT, McGough J, Shah B, Cronin P, Hong D, Aman MG, 95. Safer DJ, Zito JM: Treatment-emergent adverse events from se-
Arnold LE, Lindsay R, Nash P, Hollway J, McDougle CJ, Posey lective serotonin reuptake inhibitors by age group: children
D, Swiezy N, Kohn A, Scahill L, Martin A, Koenig K, Volkmar F, versus adolescents. J Child Adolesc Psychopharmacol 2006;
Carroll D, Lancor A, Tierney E, Ghuman J, Gonzalez NM, Grados 16:159–169
M, Vitiello B, Ritz L, Davies M, Robinson J, McMahon D: Risperi- 96. Galanter CA, Carlson GA, Jensen PS, Greenhill LL, Davies M, Li
done in children with autism and serious behavioral problems. W, Chuang SZ, Elliot GR, Arnold LE, March JS, Hechtman L, Pel-
N Engl J Med 2002; 347:314–321 ham WE, Swanson JM: Response to methylphenidate in chil-
79. Pandina GJ, Aman MG, Findling RL: Risperidone in the man- dren with attention deficit hyperactivity disorder and manic
agement of disruptive behavior disorders. J Child Adolesc Psy- symptoms in the multimodal treatment study of children with
chopharmacol 2006; 16:379–392 attention deficit hyperactivity disorder titration trial. J Child
80. Dickstein DP, Towbin KE, Van Der Veen JW, Rich BA, Brotman Adolesc Psychopharmacol 2003; 13:123–136
MA, Knopf L, Onelio L, Pine DS, Leibenluft E: Randomized 97. Carlson GA, Loney J, Salisbury H, Kramer JR, Arthur C: Stimulant
double-blind placebo-controlled trial of lithium in youths with treatment in young boys with symptoms suggesting childhood

Am J Psychiatry 168:2, February 2011 ajp.psychiatryonline.org 141

SEVERE MOOD DYSREGULATION, IRRITABILITY, AND BIPOLAR DISORDER IN YOUTHS

mania: a report from a longitudinal study. J Child Adolesc Psy- 100. Fristad MA, Verducci JS, Walters K, Young ME: Impact of mul-
chopharmacol 2000; 10:175–184 tifamily psychoeducational psychotherapy in treating children
98. Lochman JE, Barry TD, Pardini DA: Anger control training for aged 8 to 12 years with mood disorders. Arch Gen Psychiatry
aggressive youth, in Evidence-Based Psychotherapies for Chil- 2009; 66:1013–1021
dren and Adolescents. Edited by Kazdin AE, Weisz JR. New 101. West AE, Pavuluri MN: Psychosocial treatments for childhood
York, Guilford, 2003, pp 263–281 and adolescent bipolar disorder. Child Adolesc Psychiatr Clin N
99. Zonnevylle-Bender MJ, Matthys W, van de Wiel NM, Lochman Am 2009; 18:471–482
JE: Preventive effects of treatment of disruptive behavior dis- 102. American Psychiatric Association: DSM-5 Development: Pro-
order in middle childhood on substance use and delinquent posed Revisions. http://www.dsm5.org/ProposedRevisions/
behavior. J Am Acad Child Adolesc Psychiatry 2007; 46:33–39 Pages/proposedrevision.aspx?rid=397

142 ajp.psychiatryonline.org Am J Psychiatry 168:2, February 2011