Reviews and Overviews

Mechanisms of Psychiatric Illness

The Nature of the Association Between Childhood

ADHD and the Development of Bipolar Disorder:
A Review of Prospective High-Risk Studies
Anne Duffy, M.D., F.R.C.P.C.
Objective: The author reviewed pro-
spective longitudinal studies of the off-
spring of parents with bipolar disorder to
inform our understanding of the nature
of the association between childhood ADHD
and the risk of developing bipolar disorder
in adolescence and young adulthood.
Method: A literature review of published
prospective cohort studies of the offspring
of bipolar parents since 1985 was un-
dertaken using a comprehensive search
strategy in several electronic databases.
The author provides a qualitative synthe-
sis of results focusing on ADHD and the
association with bipolar disorder in pro-
spectively assessed high-risk offspring.
These results are discussed in light of
findings from other prospective epidemi-
ological and clinical cohort studies.
Results: From the reviewed high-risk studies,
evidence suggests that the clinical diagnosis
of childhood ADHD is not a reliable pre-
dictor of the development of bipolar disor-
der. However, the author found evidence
that symptoms of inattention may be part
of a mixed clinical presentation during the
early stages of evolving bipolar disorder
in high-risk offspring, appearing alongside
anxiety and depressive symptoms. The
author also found preliminary evidence
that childhood ADHD may form part of
a neurodevelopmental phenotype in off-
spring at risk for developing a subtype of
bipolar disorder unresponsive to lithium
stabilization.
Conclusions: While childhood ADHD does
not appear to be part of the typical develop-
mental illness trajectory of bipolar disorder,
subjective problems with attention can
form part of the early course, while neuro-
developmental abnormalities may be ante-
cedents in a subgroup of high-risk children.

(Am J Psychiatry 2012; 169:1247–1255)

O ne of the most important recent observations in

psychiatry came from the Dunedin longitudinal cohort
study—namely, that the majority (almost 75%) of adults
affected with psychiatric disorders had diagnosable psy-
chiatric syndromes before age 18, and almost half before
age 15 (1). Furthermore, the nature of antecedent child-
hood psychopathology was often different from that of the
adult disorder (heterotypic development). These findings
emphasized that a substantial number of adult psychiatric
disorders manifest clinically much earlier in development,
although the childhood presentation may not resemble
the full-blown adult disorder. Therefore, the challenge for
those involved in early detection and intervention is to
map the developmental trajectory of major psychiatric
disorders from the earliest reliable antecedents. The most
effective research paradigm to accomplish this goal is to
prospectively study high-risk children over the course of
development and into early adulthood.
The results of longitudinal prospective studies of high-
risk youths have already highlighted shortcomings of
the current diagnostic classification systems, which were
primarily designed to describe end-stage rather than evolv-
ing disorders. Outside of research protocols, there is no
systematic language or consensus criteria to describe the
evolution of major psychiatric disorders over the course of
development. Rather, antecedents are treated as separate
conditions, adding to the variety of meanings of the term
“comorbid” (2). As discussed by Robins (3), from DSM-III
onward, multiple diagnoses in a single patient have been
allowed, even when the symptoms fit within a single
diagnostic category, while temporal relationships between
conditions have been ignored. This approach contradicts
the principle applied elsewhere in medicine; namely that
the presentation is subsumed under one diagnosis unless
evidence proves otherwise. What is not clear is the nature
of the association between comorbid conditions within
individuals, which likely includes 1) different manifesta-
tions (during development and over the course of illness)
of a common etiological process, 2) complications of
a primary illness, 3) different illness subtypes (different

This article is the subject of a CME course (p. 1333)

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CHILDHOOD ADHD AND THE DEVELOPMENT OF BIPOLAR DISORDER
etiology), and 4) artifact associated with a splitting rather
than a lumping diagnostic convention. The key point for
this article is that the temporal pattern of psychopathology
is important in informing our understanding of differential
illness trajectories in high-risk youth.
A developmental approach to mapping the natural his-
tory of bipolar disorder has been a major research focus
worldwide for over 20 years. Given that bipolar disorder
has a substantial genetic component with an estimated
heritability of around 85% (4), and that onset occurs in
adolescence or young adulthood, children of affected pa-
rents represent a readily identifiable high-risk group that
is uniquely well suited to longitudinal research. Assuming
that there is confidence about the bipolar diagnosis in
the parent, longitudinal prospective assessment of the
offspring into adulthood allows for the identification of
antecedent vulnerabilities and the characterization of the
early course, while minimizing important confounds, in-
cluding instability of diagnoses in young clinical samples
(5) and burden-of-illness effects (repeated episodes, psy-
chosis, substance use, treatment, and medical illness) (6).
Several published longitudinal prospective studies of
offspring of bipolar parents have led to the convergent
observation that the index hypomanic or manic episode
is often preceded by childhood anxiety, sleep, and de-
pressive disorders in early adolescence. These observa-
tions are further supported by findings from a number of
cross-sectional high-risk studies reporting a wide variety
of lifetime disorders in offspring of bipolar parents (for
reviews, see Delbello and Geller [7], Lapalme et al. [8], and
Duffy [9]). What remains a subject of debate is whether or
not ADHD is a reliable childhood antecedent predicting
the development of bipolar disorder. This question arose
in part from observations of a high rate of “manic-like”
symptoms in clinical samples of children with ADHD (10,
11), a high rate of ADHD in clinically referred children
with ultra-rapid cycling bipolar disorder (12), and a high
rate of comorbidity in some cross-sectional studies of
children of bipolar parents (13). However, the diagnosis
of mania in clinically referred pediatric samples is a point
of debate (14), and elevated rates of comorbid ADHD and
bipolar disorder are not consistently found in pediatric
clinical (15) or high-risk study cohorts (16, 17).
My aim in this article is to clarify the nature of the
debated association between ADHD and bipolar disorder
by reviewing findings from prospective longitudinal
studies of children and adolescents at familial risk of
bipolar disorder and to discuss these findings in light of
those from complementary prospective epidemiological
and clinical cohort studies. I then propose an integrative
model of these illness trajectories highlighting areas of
clinical overlap and differentiation.
Method
Longitudinal and prospective studies were included in this
review if they were published cohort studies of offspring of
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a parent with confirmed bipolar disorder and if they reported on
rates of psychopathology among the offspring. A comprehen-
sive search strategy involving combinations of Medical Subject
Headings (ADHD, bipolar disorder, children of bipolar parents,
cohort studies) and title and abstract terms (bipolar, mood
disorder, major affective disorder offspring, child, adolescent,
longitudinal prospective, attention deficit) was conducted in
MEDLINE, Embase, and PsycINFO. The search was restricted to
publications after January 1985. Reference searching was also
conducted in all included studies.
Results
Characteristics of Included Studies
The literature search identified nine studies that met
inclusion criteria for review (Table 1). Recruitment and
selection criteria as well as the methods employed to
evaluate psychopathology in the parent and offspring
differed among the studies, as detailed elsewhere (18).
However, most studies used semistructured clinical in-
terviews of both the parent and offspring, conducted
by interviewers initially blind to family affiliation, and
consensus diagnostic procedures to arrive at DSM di-
agnoses. Some studies included other informants (e.g.,
teachers) and used standardized questionnaires to mea-
sure attentional, behavioral, and emotional symptom
levels. Two of the included studies were limited by
relatively short follow-up periods and small high-risk
offspring samples and are not formally discussed here
(19, 20). Other studies were more informative given the
comparison groups included (21, 22) and the detailed
prospective clinical assessments of referred youths (23,
24). The remaining studies report on larger samples of
offspring who had a parent with well-characterized bipolar
disorder and who were followed on average for at least
5 years into adolescence and adulthood (25–27).
Review of Prospective High-Risk Studies
Laroche et al. (23, 28) published findings from a 3- to 7-
year prospective follow-up study reporting on 37 off-
spring from 21 families with a bipolar parent selected
from an outpatient clinic; there were no control families
for comparison. The bipolar parent had to have been
maintained on lithium for at least 1 year and have
children between 5 and 18 years old. At the time of last
assessment, the mean age of offspring was 16.2 years
(range58–25 years). DSM diagnoses were made in 24% of
the offspring (N59/37) and clustered in the affective/
internalizing domain. While no cases of full-threshold
ADHD were diagnosed, the study reported significantly
higher scores in hyperactive, anxiety, neurotic, and de-
pression symptoms in the high-risk offspring who had
a DSM diagnosis (mostly mood and anxiety disorders)
compared with those who did not. These findings suggest
that early in the course of evolving bipolar disorder,
anxiety and minor depressive disorders dominate and that
inattention symptoms may occur in the context of the
evolving mood disorder.
Am J Psychiatry 169:12, December 2012
 ANNE DUFFY

TABLE 1. Prospective Longitudinal Studies of the Offspring of Bipolar Parents Published Between 1985 and 2011
Mean Age at Range of Age Duration of
Authors N % Female Recruitment at Recruitment Follow-Up Lifetime Rate of ADHD
Akiskal et al. (24) 68 43 Juveniles Mean53 years 5.9% high risk
(#24 years old)
Duffy et al. 216 60 16.5 years 8–25 Mean55.5 years 8% high risk; 3% control
(25, 33–36) (up to 15 years)
Hammen et al. (22) 18 56 13.6 years 8–16 Up to 3 years 6% high risk; 5% control
Hillegers et al. 140 49 16.1 years 12–21 5 years 5% high risk
(16, 26, 32)
Laroche et al. 39 36 11.4 years 5–18 3–7 years 0% high risk
(23, 28)
Nurnberger et al. (19) 53 55 19.5 years 15–25 Up to 2 years ADHD in one out of five
affected high risk
Radke-Yarrow et al. 44 50 Stratified into 3 years; 23 yearsa 0% high risk; 0% control
(21), Meyer et al.a 1.5–3.5 and
(29) 5–8 years
Shaw et al. (27, 31) 100 52 Mean 7.5 years 10 years “ADHD relatively absent”
(most ,14)
Zahn-Waxler et al. 7 0 Up to 2 years Up to 4 years 0% high risk; 0% control
(20)
a
Dynamic cohort that included some of the original families.

Radke-Yarrow et al. (21) reported on a community co-
hort of children of affectively ill and well mothers after
3 years of prospective follow-up. Two siblings from 100
families were included, one in infancy (1.5–3.5 years old)
and the other in early childhood (5–8 years old). An
association between disruptive behavior disorders and
families under higher stress (x257.05, p,0.01) and from
lower socioeconomic status (x257.46, p,0.02) was re-
ported. Children of affectively ill mothers were more likely
to manifest problems with depression symptoms in middle
(x2518.69, p,0.0001) and in later childhood (x2510.77,
p,0.0001). Anxiety disorders were identified in infancy
and early childhood in offspring of both healthy and
depressed mothers, whereas anxiety did not become
frequent until later childhood in offspring of bipolar
mothers. In summary, it became evident that children of
depressed mothers were the most severely affected with
psychiatric problems across internalizing and externaliz-
ing domains from preschool through early and later
childhood. Children of bipolar mothers held an interme-
diate position, with psychiatric and behavioral problems
becoming evident in middle and later childhood. A gender
effect, with boys showing more disruptive problems and
girls more internalizing problems, was also reported.
In subsequent years, this cohort was followed up in
adolescence (11–19 years old) and again in young adult-
hood (18–28 years old), with some families joining the
study, some changing category, and others leaving the
study. Main findings reported by Meyer et al. (29) included
that 19% (N56/32) of the offspring of bipolar mothers
and 7% (N53/42) of the offspring from unipolar mothers
developed bipolar disorder at a mean age of 16.6 years.
Based on rating scales, the study found a higher rate of
childhood attention and behavioral symptoms in the off-
spring who developed bipolar disorder relative to those
with no mood disorder in adulthood. The authors also
reported that specific deficits in executive functioning
during adolescence (as evidenced by certain parame-
ters on the Wisconsin Card Sorting Test) and premorbid
attention problems preceded the formal diagnosis and
treatment of bipolar disorder. All offspring with both
childhood attention problems and executive functioning
deficits in adolescence were diagnosed with bipolar dis-
order. These findings are limited by the small number of
cases of bipolar disorder and by the degree of assortative
mating in the families. Nonetheless, they are consistent
with the interpretation that in at least some high-risk
children, cognitive antecedents, but not a clinical diag-
nosis of ADHD, are associated with a subsequent risk of
developing bipolar disorder.
In a prospective study of school-age children (8–16 years
old) of mothers with bipolar disorder, depression, chronic
medical illness, or mothers who were healthy, Hammen
et al. (22, 30) reported on psychopathology and psycho-
social problems (based on the Child Behavior Checklist
completed by the mother and a teacher) at baseline and at
6-month intervals until age 3 years. ADHD was diagnosed
in 6% of offspring of bipolar mothers compared with 9%
of offspring of depressed mothers and 5% of offspring of
healthy comparison mothers. A substantial proportion of
the psychopathology of the offspring of bipolar mothers
was milder than that of the offspring of depressed
mothers, with anxiety disorders being prominent. Based
on maternal and teacher reports, there was no difference
in social competence, school behavior scores, or aca-
demic performance ratings between the children of bipolar
mothers and the children of healthy mothers (30). While
limited by the relatively small number of children followed
for up to 3 years, the findings are consistent with the
interpretation that ADHD is not overly represented among

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CHILDHOOD ADHD AND THE DEVELOPMENT OF BIPOLAR DISORDER
the offspring of bipolar mothers and that the early psy-
chosocial and school functioning of these high-risk off-
spring is generally comparable to that of the healthy
population and different from that of children of depressed
mothers.
Akiskal et al. (24) charted the prospective course of
evolving psychopathology in 68 referred (symptomatic)
juvenile relatives (offspring and siblings) of adult patients
with confirmed bipolar disorder who were assessed and
treated in a specialty mood disorders outpatient clinic. At
baseline, 44 of the 68 high-risk youths had been previously
seen by child mental health professionals, and 16 had been
diagnosed with emotional problems related to family or
peers, eight with neurotic (anxiety) disorders, seven with
conduct disorder, seven with schizophrenia, and four with
ADHD. Interestingly, none of the offspring assessed in
childhood were thought to have a primary mood disorder.
Within the first year of prospective study, 24 youths were
diagnosed with major depression, 11 with manic or mixed
episodes, and 22 with subaffective disorders. After an aver-
age of 3 years of prospective study, recurrences occurred
in those with major affective disorders as well as con-
version from subaffective to major affective and from
unipolar to bipolar spectrum. In summary, nonaffective
childhood diagnoses preceded the onset of minor and
major mood disorders. Depressive and subaffective dis-
orders predominated early in the course, while full-blown
hypomanic and manic episodes were not seen until after
age 13. Finally, similar to the findings of Laroche et al. (28),
childhood antecedents of “hyperactivity” and “antisocial”
symptoms were described as “phasic,” occurring along-
side mood symptoms and not responsive to trials of
stimulant medication.
Egeland et al. reported on a prospective study of school-
age children of Amish parents affected with bipolar dis-
order (100 children) and healthy parents (110 children)
who were systematically assessed at 7 years (31) and 10
years (27) after baseline. The study evolved from research
involving the adult Amish bipolar disorder patients, who
estimated that their illness manifested 9 to 12 years earlier
than the age at onset of the full-blown diagnosis. The goal
was to identify which childhood symptoms predicted the
development of bipolar disorder in the children at genetic
risk. All families were from the Amish community and
comprised a high-risk group (one bipolar parent and one
well parent), a comparison group with positive family
history (one well sibling of the bipolar disorder proband
and the other well parent), and a comparison group with
negative family history (two well parents and no relatives
with bipolar disorder). After 7 years of prospective follow-
up, 38% of the offspring of bipolar parents were tagged as
being at risk based on symptom profiles, compared with
17% of the offspring from comparison families (83% from
the positive family history subgroup). The specific clinical
risk features flagged in the children of bipolar parents
included anxious/worried, attention poor/distractible
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in school, low energy, excited, hyper alert, mood changes/
labile, school role impairment, sensitivity, somatic complaints,
and stubborn/determined. There was also evidence of a
phasic nature of the symptoms involving mood, energy,
sleep, and temper problems.
At the 10-year follow-up, the mean age of the offspring
groups was 17–18 years, and 41% of the offspring of bipolar
parents were tagged as being at risk based on symptom
profiles, compared with 16% of the offspring from com-
parison families (82% from the positive family history
subgroup). The same core symptoms remained at higher
frequency in the high-risk offspring except that low
energy, anger, fearfulness, and sensitivity dropped below
significance level, while high energy, sleep difficulties,
excessive talking, loud talking, and problems with think-
ing and concentration reached significance. Taken to-
gether, these findings suggest that during development,
putative prodromal features in high-risk offspring shifted
from anxiety-depressive to more manic symptoms. Dis-
tractibility, stubbornness, and being easily upset were
first noted early in childhood, alongside the affective
symptoms, whereas “problem concentrating” was asso-
ciated with manic-like symptom clusters later in devel-
opment. The episodic nature of these symptom clusters
continued throughout development. Furthermore, the
authors confirmed that ADHD as a syndrome was “rela-
tively absent.”
An ongoing prospective study of 140 children of bipo-
lar parents in the Netherlands, reported by Wals et al.
(16, 26, 32), builds on the findings of the previously de-
scribed studies. The majority of families (102 children;
mean age516.1 years) derived from a community-based
Dutch Patient Association, while the others were identified
through outpatient clinics. High-risk families had compa-
rable socioeconomic status and higher IQs on average
compared with those of the Dutch general population, and
76% of families were intact. While symptom rating scales
were generally comparable between the high-risk group
and the normative population, daughters of bipolar parents
had higher scores on Child Behavior Checklist subscales
for total problems, internalizing, externalizing, somatic
complaints, anxious/depressed, social problems, delin-
quent behavior, and aggressive behavior. Sons of bipolar
parents scored higher on Child Behavior Checklist sub-
scales of total problems, externalizing, thought problems,
and aggressive behavior. On self-report, high-risk older
adolescent girls reported more attention problems, while
teachers reported no differences in attention or behavior
problems in the high-risk boys or girls compared with the
normative population.
At last follow-up, covering almost 5 years, the cohort had
129 children, with a mean age of 20.8 years (26). The risk of
ADHD over the prospective waves of assessment remained
stable, while the risk of mood disorder and bipolar dis-
order increased. The lifetime risk was 10% for bipolar dis-
order (I or II), 40% for any diagnosable mood disorder, and
Am J Psychiatry 169:12, December 2012

5% for ADHD. In those high-risk offspring with bipolar
disorder, the index mood diagnosis was almost always
depressive in polarity, at a mean age of 13.4 years (SD54.2),
and the index hypomanic/manic episode manifested a
mean of 4.9 years (SD53.4) later (at 18.4 years old). Only
one of these 13 bipolar subjects had treatment with sti-
mulant medication before the development of the acti-
vated episode. Collectively, these findings lend further
support to reports of a variety of emotional and behavioral
childhood antecedents followed by subaffective and de-
pressive disorders in early adolescence, and hypomanic/
manic episodes later in life. ADHD, as a clinical diagnosis,
was not higher in the high-risk offspring than in the gen-
eral population based on either clinical interview assess-
ment or teacher reports.
Finally, our group has published several reports from an
ongoing longitudinal high-risk study (33–36). The high-risk
families (one affected and one well parent) were selected
through specialty clinical research programs and diag-
nosed based on best estimate procedure. Bipolar parents
were divided on the basis of an unequivocal response or
nonresponse to long-term lithium treatment. Lithium res-
ponse identifies a more homogeneous subtype of classi-
cal bipolar disorder (37), while lithium nonresponse is
characterized by a chronic illness course and a higher
familial risk of psychotic disorders (38).
Early on, we reported an association in the high-risk
offspring between subjective problems in attention and
symptoms of depression that was not related to any
obvious deficit in sustained attention on psychological
testing (39). In subsequent analyses, our group found
comparable lifetime rates of clinically significant ADHD
(often comorbid with learning disabilities) in high-risk
(8.3%) and comparison offspring (5.8%) (25). The current
age-adjusted lifetime risk of major affective disorders
in 231 high-risk offspring at a mean age of 25.7 years old
(SD59.23) is estimated at 52.8% (mean age at onset516.8
years) and bipolar disorder at 13.5%. Interestingly, higher
rates of ADHD and other neurodevelopmental abnor-
malities, including learning disabilities and cluster A traits,
were observed in the subgroup of offspring of parents
who did not respond to lithium (35). Furthermore, a
recent analysis (40) found that this neurodevelopmental
phenotype was more frequently observed in high-risk
offspring who developed a substance use disorder com-
pared with those who did not (18.0% compared with
9.3%, p50.06). While limited by a small sample, across
this high-risk cohort, ADHD does not appear to be a
robust predictor of major affective disorder or bipolar
disorder. Of those high-risk offspring with a childhood
diagnosis of ADHD, 28% have so far gone on to develop
a major affective disorder (major depression or bipolar I or
II) and 11% a minor affective disorder (dysthymia or de-
pression not otherwise specified), while 93% of the high-
risk offspring with a major affective diagnosis did not have
antecedent ADHD.
Am J Psychiatry 169:12, December 2012
ANNE DUFFY
Conclusions
Major Findings
While this qualitative review is limited by the number
of prospective longitudinal high-risk studies collectively
assessing a relatively small number of bipolar-affected
offspring, the findings are consistent across studies. One
major finding from this review is that childhood ADHD
does not appear to be significantly overrepresented
among the offspring of parents with well-characterized
bipolar disorder compared with offspring of healthy
parents or with the risk of ADHD in the general pop-
ulation. Furthermore, although the data remain limited,
there does not appear to be an association between ADHD
as a childhood diagnosis and the subsequent risk of bipolar
disorder in the high-risk offspring. Therefore, it seems rea-
sonable to conclude that the clinical diagnosis of ADHD
does not appear to be a reliable antecedent in the devel-
opmental trajectory toward bipolar disorder.
However, the risk of ADHD in the studies reviewed may
have been influenced by the high rate of intactness and
relatively high socioeconomic status of the high-risk fami-
lies. This speculation is indirectly supported by the find-
ings of Birmaher and colleagues (17), who reported in a
cross-sectional study of school-age children that rates of
ADHD were not elevated among the offspring of bipo-
lar parents relative to comparison subjects after adjust-
ing for confounding variables (i.e., socioeconomic status
and non-bipolar disorder psychopathology in biological
parents), suggesting that ADHD may be more related to
the general burden of psychopathology in the families,
rather than specifically to the risk of bipolar disorder.
Indirect support also comes from Radke-Yarrow et al. (21),
who reported an association between higher rates of
disruptive behavior disorders in offspring from high-risk
families of lower socioeconomic status and those with
more stress.
An additional influence may have been the low rate
of psychopathology in the nonproband parents and low
comorbidity rates (especially of substance use and con-
duct disorders) in the bipolar parents in some of the re-
viewed studies (26, 27, 36). Furthermore, a number of the
high-risk studies reviewed here included affected parents
with a more classical form of bipolar disorder that was
completely responsive to or at least stabilized by lithium
and not typically associated with ADHD (23, 25, 31). For
example, among the Amish parent probands, ADHD was
relatively absent based on expert clinician retrospective
review of all available clinical information (31).
However, attentional and cognitive symptoms and pro-
blems were reported by high-risk subjects and other in-
formants (typically parents) in a number of the studies
reviewed here, consistent with a vulnerability trait in some
or as part of the early course of an evolving major affective
disorder in others. For example, in the findings reported by
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CHILDHOOD ADHD AND THE DEVELOPMENT OF BIPOLAR DISORDER
Duffy et al. (25, 35), ADHD was seen at an increased rate in
offspring of parents with a psychotic spectrum bipolar
disorder that failed to stabilize with lithium. A number of
these children were diagnosed with full-blown ADHD by a
child and adolescent psychiatrist and went on to develop
a diagnosable affective disorder in adolescence. The course
of the mood disorder in these offspring (as in the parent)
tended to be nonepisodic, with residual symptoms between
acute episodes, and adult relatives had a differentially higher
loading of chronic psychotic disorders. Preliminary findings
suggest that ADHD may form part of a neurodevelopmen-
tal childhood phenotype predicting a particular subtype
of bipolar disorder. In other words, bipolar disorder is
known to be a heterogeneous diagnosis, and some subtypes
appear to overlap clinically and biologically with psychotic
spectrum disorders (41).
On the other hand, a number of studies reviewed here
reported that problems with attention and distractibility
manifest in high-risk offspring as part of a childhood in-
ternalizing condition. Furthermore, an important aspect
documented in several studies has been the periodic na-
ture of these early mixed symptom clusters, which again
suggests a bipolar disorder diathesis characterized by a
recurrent illness course, rather than by a chronic course, as
would be expected in the case of a typical developmental
disorder like ADHD. Therefore, in children at confirmed
familial risk for the development of bipolar disorder,
childhood ADHD may not be a clinical antecedent per se,
but rather symptoms of inattention and distractibility
may form part of an early subaffective clinical presentation
on the trajectory toward bipolar disorder.
Prospective Studies of Clinically
and Community-Referred Children
Given the limitations of the high-risk data reviewed
here, findings from complementary prospective studies of
other cohorts of children can inform the interpretation of
the findings from this review. There have been several
large prospective studies of epidemiological samples. One
of these is the Dunedin longitudinal birth cohort study,
which followed 1,037 children with assessment points
through childhood, adolescence, and early adulthood. In
the Dunedin study, adults diagnosed with mania were
more likely than those without mania to have a history of
juvenile conduct or oppositional disorder and depression,
but not ADHD (1). The authors noted that many adults
with bipolar disorder had antecedent childhood anxiety
disorders, but this association fell short of statistical sig-
nificance. Interestingly, adults with schizophreniform
disorders had a juvenile history of a number of disorders
including ADHD. In a subsequent report on this cohort
(42), schizophreniform disorder was associated with neu-
rodevelopmental and cognitive abnormalities during
childhood, while adults with bipolar disorder had com-
parable motor, language, and cognitive performance in
childhood to that of healthy comparison subjects. These
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observations add to the substantial evidence from pro-
spective studies of psychological and neurological ab-
normalities in children who go on to develop adult
schizophrenia, contrasting with the normal or advanced
premorbid intellectual functioning and school perfor-
mance generally found in children who develop bipolar
disorder in adulthood (41, 43).
Another such study, the Oregon Adolescent Depression
Project, followed a cohort of 1,709 high school students
from representative urban and rural school districts as-
sessed at four time points from adolescence to early
adulthood. This cohort had a very low rate of full-blown
bipolar disorder, while subthreshold bipolar disorder
symptoms were more common but transient. In a sub-
sequent analysis investigating the relationship of sub-
threshold conditions to the subsequent development of
full-blown disorders, Shankman et al. (44) reported that
with the exception of ADHD and bipolar disorder, there was
an increased probability of escalating to full syndrome dis-
orders (homotypic continuity). In the case of heterotypic
continuity, individual externalizing subthreshold condi-
tions predicted the development of other full-syndrome
externalizing conditions (i.e., associations between ADHD,
conduct, and substance use disorders), but not the de-
velopment of internalizing disorders or bipolar disorder.
Finally, a recent analyses from the German Early De-
velopmental Stages of Psychopathology prospective
study confirmed that hypomanic symptoms were common
and mostly transitory in the general adolescent population
(45). Almost 40% of 1,565 participants expressed bipolar
symptoms at one assessment, but only 17% experienced
these symptoms at two assessment times (46). In an
analysis of the association between risk factors, including
ADHD, and the onset and persistence of subthreshold
manic and depressive symptoms, cannabis use was asso-
ciated with the onset of manic symptoms (odds ratio54.26;
p50.010), while ADHD was associated with the persistence
of depressive symptoms (45). Therefore, findings suggest
that hypomanic symptoms are often a normative tran-
sient experience in adolescence and that ADHD does not
appear to be a risk factor in the general population for
the development of subthreshold or full-blown bipolar
disorder.
There have been differing reports on comorbidity rates
between ADHD and bipolar disorder in pediatric clinical
cohorts, particularly in very young referred children
thought to be manic (47). As pointed out by Carlson (14),
some of this variation may be due to assessment and
sampling issues, as well as to differences in the concep-
tualization and approach to diagnosis. Specifically, U.S.
research groups typically prefer standardized interviews
emphasizing individual symptoms, while U.K. research
groups tend to adopt a clinical approach emphasizing
patterns of symptoms.
Recently, Wozniak et al. (48) reported on the persistence
of bipolar disorder after 4 years of prospective study in 78
Am J Psychiatry 169:12, December 2012

FIGURE 1. Developmental Trajectories of ADHD and Bipolar Disorder
ADHD
Oppositional
School problems
Emotional Cognitive Substance
symptoms deficitsa abuse
Depressive and
Anxiety disorders Adjustment
disorders
Childhood Adolescence
a
Subthreshold symptoms in a subset at risk for bipolar disorder unresponsive to lithium.
b
Episodic subthreshold symptoms in evolving bipolar disorder.
youths with a mean age of 13.4 years at last assessment
and an estimated age of 4.9 years at onset of bipolar I
disorder. These youths, primarily boys with comorbid
ADHD, were ascertained from a tertiary care psychophar-
macology clinic that specializes in the treatment of ADHD.
The course of bipolar disorder was mostly chronic, and
only five children were in remission at last follow-up.
Other reports of persistent manic-like presentations have
been published (10, 47), and most of these reports show
a high rate of comorbidity with ADHD, externalizing
disorders, or pervasive developmental disorders. As re-
viewed recently by Leibenluft (49), some of these presen-
tations have been recast as fitting criteria for severe mood
dysregulation disorder and on prospective follow-up
have not shown continuity with adult bipolar disorder.
On the other hand, prospective studies of children with
primary ADHD have been very consistent in supporting
the findings of prospective epidemiological studies,
namely, that ADHD in children is associated with a
greater risk of antisocial behavior, criminal activity, con-
duct disorder, and substance use disorders in adoles-
cence and adulthood, but not to an elevated risk of
bipolar disorder (50, 51).
Toward an Integrative Developmental Model
of ADHD and Bipolar Disorder
In the end, prospective longitudinal studies provide very
little evidence that ADHD is a reliable antecedent to the
development of bipolar disorder that continues into adult-
hood. In fact, substantial evidence has been reported from
prospective cohort studies of increasingly different illness
trajectories of ADHD and bipolar disorder over the course
of development from a starting place of some overlapping
Am J Psychiatry 169:12, December 2012
ANNE DUFFY
ADHD ADHD
Conduct Sociopathy
disorders Substance use
Energetic
Distractible
Impulsiveb
Bipolar disorder
Substance use
Early Adulthood
nonspecific symptoms early in childhood (Figure 1).
Trajectories do not suggest that all children with ADHD
will go on to have persistent ADHD or to develop com-
plications or related disorders such as conduct or sub-
stance use disorders or sociopathy as adults, but rather
these are outcomes of increased risk in this population.
Similarly, it is not that all offspring of parents with bipolar
disorder will manifest early childhood antecedents such as
anxiety disorders or will develop sensitivity to stress or
depressive disorders in early adolescence, followed later
by activated episodes. However, this predictive clinical
sequence reflects a risk probability derived from pro-
spective studies.
The other important observation from prospective high-
risk studies is that early in development and in the clinical
course, symptoms appear to be nonspecific and often
overlap between different evolving disorders; in the case
of bipolar disorder and ADHD, impulsivity, labile mood,
and internalizing symptoms (anxiety and depression) are
not uncommon in childhood. Furthermore, in a selected
subset of children from bipolar parents with a high rate
of psychosis in family members and whose illness did
not respond to lithium prophylaxis, ADHD and learning
disabilities may form part of an early neurodevelop-
mental phenotype that overlaps somewhat with the early
presentation in children with primary ADHD. However,
the temporal pattern of psychopathology against the
backdrop of differential familial risk sheds light on the
increasingly different illness trajectories, presumably
reflecting shared as well as different underlying patho-
physiological processes.
Longitudinal prospective research in large community
and selected high-risk cohorts has been immensely helpful
ajp.psychiatryonline.org 1253
CHILDHOOD ADHD AND THE DEVELOPMENT OF BIPOLAR DISORDER
in mapping the early natural history of major psychiatric
disorders and in highlighting both homotypic and hetero-
typic developmental continuity of psychopathology over
the course of illness development. Mapping the early
clinical course is the first step in advancing studies of the
associated neurobiological pathways and identifying novel
targets for early intervention. Our diagnostic systems and
approaches can catch up to the progress that prospective
research has made by emphasizing the need, as in other
areas of medicine, to incorporate the developmental
trajectory against the backdrop of risk as indicated by
the family history of psychiatric disorders, in order to im-
prove the accuracy and validity of psychiatric diagnosis in
symptomatic youths.
Received Nov. 24, 2011; revisions received April 16, May 9, and
May 22, 2012; accepted May 29, 2012 (doi: 10.1176/appi.ajp.2012.
11111725). From the Department of Psychiatry, University of Calgary,
Alberta, Canada. Address correspondence to Dr. Duffy (acduffy@
ucalgary.ca).
Dr. Duffy has received personal support awards from the Brain and
Behaviour Research Foundation (NARSAD Young and Intermediate
Investigator Awards), from the Canadian Institutes of Health Research
(Young Investigator Award), and from the Canada Research Chairs
Program.
Supported by an operating grant from the Canadian Institutes of
Health Research (MOP 102761).
The author thanks Sarah Doucette for assistance with the table and
figure and proofreading the manuscript.
References
1. Kim-Cohen J, Caspi A, Moffitt TE, Harrington H, Milne BJ, Poulton
R: Prior juvenile diagnoses in adults with mental disorder: de-
velopmental follow-back of a prospective-longitudinal cohort.
Arch Gen Psychiatry 2003; 60:709–717
2. Angold A, Costello EJ, Erkanli A: Comorbidity. J Child Psychol
Psychiatry 1999; 40:57–87
3. Robins LN: How recognizing “comorbidities” in psychopathol-
ogy may lead to an improved research nosology. Clin Psychol
Sci Prac 1994; 1:93–94
4. Bienvenu OJ, Davydow DS, Kendler KS: Psychiatric “diseases”
versus behavioral disorders and degree of genetic influence.
Psychol Med 2011; 41:33–40
5. Bromet EJ, Kotov R, Fochtmann LJ, Carlson GA, Tanenberg-
Karant M, Ruggero C, Chang SW: Diagnostic shifts during the
decade following first admission for psychosis. Am J Psychiatry
2011; 168:1186–1194
6. Duffy A, Lewitzka U, Doucette S, Andreazza A, Grof P: Biological
indicators of illness risk in offspring of bipolar parents: targeting
the hypothalamic-pituitary-adrenal axis and immune system.
Early Interv Psychiatry 2012; 6:128–137
7. DelBello MP, Geller B: Review of studies of child and adolescent
offspring of bipolar parents. Bipolar Disord 2001; 3:325–334
8. Lapalme M, Hodgins S, LaRoche C: Children of parents with
bipolar disorder: a meta-analysis of risk for mental disorders.
Can J Psychiatry 1997; 42:623–631
9. Duffy A: The early natural history of bipolar disorder: what we
have learned from longitudinal high-risk research. Can J Psy-
chiatry 2010; 55:477–485
10. Wozniak J, Biederman J, Kiely K, Ablon JS, Faraone SV, Mundy E,
Mennin D: Mania-like symptoms suggestive of childhood-onset
1254 ajp.psychiatryonline.org
bipolar disorder in clinically referred children. J Am Acad Child
Adolesc Psychiatry 1995; 34:867–876
11. Biederman J, Faraone S, Mick E, Wozniak J, Chen L, Ouellette C,
Marrs A, Moore P, Garcia J, Mennin D, Lelon E: Attention-deficit
hyperactivity disorder and juvenile mania: an overlooked
comorbidity? J Am Acad Child Adolesc Psychiatry 1996; 35:
997–1008
12. Geller B, Craney JL, Bolhofner K, Nickelsburg MJ, Williams M,
Zimerman B: Two-year prospective follow-up of children with
a prepubertal and early adolescent bipolar disorder phenotype.
Am J Psychiatry 2002; 159:927–933
13. Chang KD, Steiner H, Ketter TA: Psychiatric phenomenology of
child and adolescent bipolar offspring. J Am Acad Child Adolesc
Psychiatry 2000; 39:453–460
14. Carlson GA: Will the child with mania please stand up? Br J
Psychiatry 2011; 198:171–172
15. Hassan A, Agha SS, Langley K, Thapar A: Prevalence of bipolar
disorder in children and adolescents with attention-deficit hy-
peractivity disorder. Br J Psychiatry 2011; 198:195–198
16. Wals M, Hillegers MHJ, Reichart CG, Ormel J, Nolen WA, Verhulst
FC: Prevalence of psychopathology in children of a bipolar
parent. J Am Acad Child Adolesc Psychiatry 2001; 40:1094–1102
17. Birmaher B, Axelson D, Monk K, Kalas C, Goldstein B, Hickey
MB, Obreja M, Ehmann M, Iyengar S, Shamseddeen W, Kupfer
D, Brent D: Lifetime psychiatric disorders in school-aged off-
spring of parents with bipolar disorder: the Pittsburgh Bipolar
Offspring study. Arch Gen Psychiatry 2009; 66:287–296
18. Duffy A, Doucette S, Lewitzka U, Alda M, Hajek T, Grof P: Find-
ings from bipolar offspring studies: methodology matters. Early
Interv Psychiatry 2011; 5:181–191
19. Nurnberger J, Hamovit J, Hibbs ED, Pelligrini D, Guroff JJ, Maxwell
ME, Smith A, Gershon E: A high-risk study of primary affective
disorder: selection of subjects, initial assessment, and 1-to-2 year
follow-up, in Relatives at Risk for Mental Disorders. Edited by
Dunner D, Gershon E, Barrett J. New York, Raven Press Ltd, 1988,
pp 161–177
20. Zahn-Waxler C, Mayfield A, Radke-Yarrow M, McKnew DH,
Cytryn L, Davenport YB: A follow-up investigation of offspring
of parents with bipolar disorder. Am J Psychiatry 1988; 145:
506–509
21. Radke-Yarrow M, Nottelmann E, Martinez P, Fox MB, Belmont
B: Young children of affectively ill parents: a longitudinal study
of psychosocial development. J Am Acad Child Adolesc Psychi-
atry 1992; 31:68–77
22. Hammen C, Burge D, Burney E, Adrian C: Longitudinal study of
diagnoses in children of women with unipolar and bipolar af-
fective disorder. Arch Gen Psychiatry 1990; 47:1112–1117
23. LaRoche C, Cheifetz P, Lester EP, Schibuk L, DiTommaso E,
Engelsmann F: Psychopathology in the offspring of parents with
bipolar affective disorders. Can J Psychiatry 1985; 30:337–343
24. Akiskal HS, Downs J, Jordan P, Watson S, Daugherty D, Pruitt DB:
Affective disorders in referred children and younger siblings of
manic-depressives: mode of onset and prospective course. Arch
Gen Psychiatry 1985; 42:996–1003
25. Duffy A, Alda M, Hajek T, Sherry SB, Grof P: Early stages in the
development of bipolar disorder. J Affect Disord 2010; 121:
127–135
26. Hillegers MHJ, Reichart CG, Wals M, Verhulst FC, Ormel J, Nolen
WA: Five-year prospective outcome of psychopathology in the
adolescent offspring of bipolar parents. Bipolar Disord 2005; 7:
344–350
27. Shaw JA, Egeland JA, Endicott J, Allen CR, Hostetter AM: A 10-
year prospective study of prodromal patterns for bipolar dis-
order among Amish youth. J Am Acad Child Adolesc Psychiatry
2005; 44:1104–1111
28. Laroche C, Sheiner R, Lester E, Benierakis C, Marrache M,
Engelsmann F, Cheifetz P: Children of parents with manic-
Am J Psychiatry 169:12, December 2012

depressive illness: a follow-up study. Can J Psychiatry 1987; 32:
563–569
29. Meyer SE, Carlson GA, Wiggs EA, Martinez PE, Ronsaville DS,
Klimes-Dougan B, Gold PW, Radke-Yarrow M: A prospective
study of the association among impaired executive functioning,
childhood attentional problems, and the development of bi-
polar disorder. Dev Psychopathol 2004; 16:461–476
30. Anderson CA, Hammen CL: Psychosocial outcomes of children
of unipolar depressed, bipolar, medically ill, and normal
women: a longitudinal study. J Consult Clin Psychol 1993; 61:
448–454
31. Egeland JA, Shaw JA, Endicott J, Pauls DL, Allen CR, Hostetter AM,
Sussex JN: Prospective study of prodromal features for bi-
polarity in well Amish children. J Am Acad Child Adolesc Psy-
chiatry 2003; 42:786–796
32. Reichart CG, Wals M, Hillegers MH, Ormel J, Nolen WA, Verhulst
FC: Psychopathology in the adolescent offspring of bipolar
parents. J Affect Disord 2004; 78:67–71
33. Duffy A, Alda M, Kutcher S, Fusee C, Grof P: Psychiatric symp-
toms and syndromes among adolescent children of parents
with lithium-responsive or lithium-nonresponsive bipolar dis-
order. Am J Psychiatry 1998; 155:431–433
34. Duffy A, Alda M, Kutcher S, Cavazzoni P, Robertson C, Grof E,
Grof P: A prospective study of the offspring of bipolar parents
responsive and nonresponsive to lithium treatment. J Clin Psy-
chiatry 2002; 63:1171–1178
35. Duffy A, Alda M, Crawford L, Milin R, Grof P: The early mani-
festations of bipolar disorder: a longitudinal prospective study
of the offspring of bipolar parents. Bipolar Disord 2007; 9:
828–838
36. Duffy A, Alda M, Hajek T, Grof P: Early course of bipolar disorder
in high-risk offspring: prospective study. Br J Psychiatry 2009;
195:457–458
37. Grof P, Duffy A, Alda M, Hajek T: Lithium response across gen-
erations. Acta Psychiatr Scand 2009; 120:378–385
38. Grof P, Alda M, Grof E, Zvolsky P, Walsh M: Lithium response
and genetics of affective disorders. J Affect Disord 1994; 32:
85–95
39. Duffy A, Grof P, Kutcher S, Robertson C, Alda M: Measures of
attention and hyperactivity symptoms in a high-risk sample of
children of bipolar parents. J Affect Disord 2001; 67:159–165
40. Duffy A, Horrocks J, Milin R, Doucette S, Persson G, Grof P: Ad-
olescent substance use disorder during the early stages of bi-
polar disorder: a prospective high-risk study. J Affect Disord
(Epub ahead of print, Sep 6, 2012)
Am J Psychiatry 169:12, December 2012
ANNE DUFFY
41. Demjaha A, MacCabe JH, Murray RM: How genes and environ-
mental factors determine the different neurodevelopmental
trajectories of schizophrenia and bipolar disorder. Schizophr
Bull 2012; 38:209–214
42. Cannon M, Caspi A, Moffitt TE, Harrington H, Taylor A, Murray
RM, Poulton R: Evidence for early-childhood, pan-developmental
impairment specific to schizophreniform disorder: results from
a longitudinal birth cohort. Arch Gen Psychiatry 2002; 59:449–
456
43. MacCabe JH, Lambe MP, Cnattingius S, Sham PC, David AS,
Reichenberg A, Murray RM, Hultman CM: Excellent school per-
formance at age 16 and risk of adult bipolar disorder: national
cohort study. Br J Psychiatry 2010; 196:109–115
44. Shankman SA, Lewinsohn PM, Klein DN, Small JW, Seeley JR,
Altman SE: Subthreshold conditions as precursors for full
syndrome disorders: a 15-year longitudinal study of multiple
diagnostic classes. J Child Psychol Psychiatry 2009; 50:
1485–1494
45. Tijssen MJ, Van Os J, Wittchen HU, Lieb R, Beesdo K, Wichers M:
Risk factors predicting onset and persistence of subthreshold
expression of bipolar psychopathology among youth from the
community. Acta Psychiatr Scand 2010; 122:255–266
46. Tijssen MJ, van Os J, Wittchen HU, Lieb R, Beesdo K, Mengelers
R, Wichers M: Prediction of transition from common adolescent
bipolar experiences to bipolar disorder: 10-year study. Br J
Psychiatry 2010; 196:102–108
47. Geller B, Tillman R, Bolhofner K, Zimerman B: Child bipolar
I disorder: prospective continuity with adult bipolar I dis-
order; characteristics of second and third episodes; pre-
dictors of 8-year outcome. Arch Gen Psychiatry 2008; 65:
1125–1133
48. Wozniak J, Petty CR, Schreck M, Moses A, Faraone SV, Biederman
J: High level of persistence of pediatric bipolar I disorder from
childhood onto adolescent years: a 4-year prospective longitu-
dinal follow-up study. J Psychiatr Res 2011; 45:1273–1282
49. Leibenluft E: Severe mood dysregulation, irritability, and the
diagnostic boundaries of bipolar disorder in youths. Am J Psy-
chiatry 2011; 168:129–142
50. Mannuzza S, Klein RG: Long-term prognosis in attention-deficit/
hyperactivity disorder. Child Adolesc Psychiatr Clin N Am 2000;
9:711–726
51. Langley K, Fowler T, Ford T, Thapar AK, van den Bree M, Harold
G, Owen MJ, O’Donovan MC, Thapar A: Adolescent clinical out-
comes for young people with attention-deficit hyperactivity
disorder. Br J Psychiatry 2010; 196:235–240
ajp.psychiatryonline.org 1255