Prodromal Symptoms Before Onset of Manic-Depressive

Disorder Suggested by First Hospital Admission Histories

JANICE A. EGELAND, PH.D., ABRAM M. HOSTETTER, M.D., DAVID L. PAULS, PH.D.,
AND JAMES N. SUSSEX, M.D.

ABSTRACT
Objective: A priority for research on manic-depressive or bipolar I disorder (BPI) for children and adolescents has been
to search for early predictors of the illness. Method: Medical record data were reviewed and systematically coded for a
sample of 58 adult patients (32 males/26 females) with confirmed diagnoses of BPI to identify prodromal features and
possible patterns of symptoms from the Amish Study. Results: The most frequently reported symptoms included episodic
changes in mood (depressed and irritable) and energy plus anger dyscontrol, with no significant gender differences. A pro-
gression of ages is seen for the most commonly reported symptoms prior to age 16. The time interval was 9 to 12 years
between appearance of the first symptoms and onset of a documented BPI syndrome. Conclusions: The data suggest
testable hypotheses about specific symptoms and behaviors that may be useful for the early detection of children at high-
est risk for developing manic-depressive disorder. J. Am. Acad. Child Adolesc. Psychiatry, 2000, 39(10):1245–1252. Key
Words: bipolar disorder, prodromal symptoms/behaviors.

There is increasing evidence for the occurrence of manic-
depressive or bipolar I disorder (BPI) in childhood and of
a growing public concern about better understanding
and treatment of these children (Carlson, 1995; Faedda
et al., 1995; Geller and Luby, 1997; Papolos and Papolos,
2000; Wozniak et al., 1995). Controversy remains about
the appropriateness of using criteria for adult bipolar ill-
ness for children, possible comorbid psychiatric dis-
orders, and identifying pediatric antecedents for the
syndrome (American Academy of Child and Adolescent
Psychiatry, 1997; Biederman et al., 1995; Faraone et al.,
1997; Fristad et al., 1995; Geller et al., 1995; Weller
et al., 1995). Prospective study of children at risk is the
Accepted April 13, 2000.
From the Department of Psychiatry, University of Miami School of Medicine,
Miami (J.A.E., A.M.H., J.N.S.), and Child Study Center, Yale University
School of Medicine, New Haven, CT (D.L.P.).
The Prodromal and Child and Adolescent Research and Evaluation (CARE)
Programs were supported by the Stanley Foundation of the National Alliance for
the Mentally Ill (1996–2000) and the Amish Study was funded (1976–1994)
by NIMH grant MH28287 (Dr. Egeland). Special thanks to senior staff Cleona
Allen and Susan Gravino, Dr. Jean Endicott for help in coding decisions, Dr.
Edward Ginns for manuscript critiques, and the Old Order Amish families for
23 years of cooperation.
Reprint requests to Dr. Egeland, University of Miami, North Research Office,
20 Briarcrest Square, Suite 200, Hershey, PA 17033.
0890-8567/00/3910–1245䉷2000 by the American Academy of Child
and Adolescent Psychiatry.
ideal, but retrospective data can inform about diagnosis
and early signs of illness.
In a thorough retrospective review of the literature on
pediatric cases, aged 6 to 12 years, Weller and colleagues
(1986, 1995) concluded that mania was underdiagnosed
in prepubertal children and was consistent in clinical fea-
tures with the standard DSM-III criteria. It is recognized
that many adult patients with BPI, with onset during
adolescence or later, exhibited symptoms long before
they met formal diagnostic criteria. Previous data from
the Amish Study showed that affective symptoms may
predate the onset of illness by an average of 10 years
(Egeland et al., 1987).
In a more recent study it was ascertained that 59% of
adults with BPI recalled having their first affective symp-
toms as children or adolescents (Lish et al., 1994). This was
based on the collected memories of patients sampled by
mailed questionnaires through the National Depressive and
Manic-Depressive Association (DMDA). Despite interest-
ing findings, 2 unavoidable types of bias were inherent in
such a retrospective study. The first was that adult BPI
patients with an established diagnosis would naturally
focus on symptoms apparent to them through treatment
and experience with their illness. The second limitation was
lack of a comparison group to determine whether adults
with other disorders might manifest similar symptoms.

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EGELAND ET AL.
Objective
Amish Study collaborators recognized that retrospec-
tive study of our adult bipolar sample had advantages in
addressing these limitations. If one focused on the social
history taken at the first admission to a hospital for psy-
chiatric evaluation and treatment, it would be prior to a
formal diagnosis being established. A diagnosis of bipolar
disorder often was not made until subsequent admissions
documented the course of the illness (Egeland et al.,
1983). Social history information came from an unstruc-
tured interview with no targeting of specific symptoms.
The Amish informants describing prodromal features
would not be influenced by an understanding of the ill-
ness over time. The large majority of patients (85%) were
accompanied by their parents at the time of first admis-
sion, and 68% were still single and living at home. The
informants provided spontaneous narratives about the
patient. The Amish Study also had the advantage of a
contrast group of the normal siblings. Amish patients
belong to very large sibships and are under constant
observation in a closed society. Hence, the “social history”
taken at first admission contained family observations
based on what was “different” about this patient com-
pared with peers. The objective of this study was to
abstract these intake records in a search for prodromal fea-
tures in childhood and early adolescent preonset periods.
The Amish Study has used 2 methods of case ascer-
tainment, one being an institutional search of psychiatric
records from local hospitals and the second a community-
based epidemiological survey using family informants in
all Amish church districts. Cases of mental illness continue
to be reported by multiple sources. Diagnostic evaluation
is based on data from both abstracted medical records and
detailed psychiatric interviews. More than 300 cases have
been diagnosed, independently, by a 5-member panel of
psychiatrists according to strict Research Diagnostic
Criteria (RDC) (Egeland et al., 1990; Hostetter et al.,
1983; Spitzer et al., 1978). The psychiatric panel evaluated
cases blind to family relationships, medical record diag-
noses, and treatment. This uniform evaluation process,
spanning 23 years, has yielded a sample of 58 BPI cases
used for this report. The 58 comprise the total BPI sample
of all subjects born since 1900, actively ill during the time
frame of the study, with at least one medical record.
Bipolar disorder among the Amish compared with
non-Amish patients may differ because cultural features
can influence the expression of some symptoms, but no
1246 J . A M . A C A D . C H I L D A D O L E S C . P S YC H I AT RY, 3 9 : 10 , O C TO B E R 2 0 0 0
differences were observed with respect to the biological
parameters or response to treatment (Egeland et al., 1983;
Hauger, Faedda, Papolos, and Egeland, unpublished
course-of-illness data, 1998). Because none of the 58 cases
(32 males/26 females) was diagnosed before puberty, the
present study was initiated to capitalize on a wealth of
detailed intake observations from hospital admission
interviews. The intent of the current study was to exam-
ine these records for evidence of prodromal features of
manic-depressive disorder. All patients gave signed,
informed consent for record review.
METHOD
Three raters (A.M.H., J.N.S., J.A.E.) independently abstracted
the first admission record information for all possible prodromal or
antecedent features of the illness using a semistructured coding
“Log” designed to note the following: (1) any mention of mood; (2)
any “objective” symptoms (e.g., appetite, sleep, behavior); and (3)
any “subjective” symptoms (e.g., cognition, feelings). As indicated,
prodromal information came from the social history at first admis-
sion, with occasional comments by the family visiting during that
episode. The raters had no preconceived hypotheses about which
prodromal features might have been mentioned by the family as pre-
dating the onset of illness as defined by RDC. No checklist of pos-
sible symptoms was used. Only those symptoms and behaviors that
occurred prior to the age of onset for bipolar affective disorder were
the focus of this exercise. This age of onset by RDC had been estab-
lished for subjects previously by Amish Study investigators (Egeland
et al., 1987).
For each entry, the raters coded the age and/or developmental stage
at which the family said it occurred. Occasionally family informants
did not give a specific age for an early symptom/behavior during the
unstructured admission interview. Then guidelines were used based
on the meaning of age-graded terms among the Amish. For example,
“school years” were coded as age 8 and “Amish vocational classes and
work” as age 14 (Egeland et al., 1987). Also, the raters noted any evi-
dence that a feature was episodic. The exact words and page reference
from the admission history had to be recorded on the Log.
A few examples of the raw data from intake histories include the fol-
lowing: “about every half year since he was 10, he would become either
very withdrawn or else very high and talkative”; “at age 12 he had weak-
ness and weight loss again”; “in 3rd grade the teacher noticed she began
to seem sad at school and cried when the children sang”; “he com-
plained of belly aches and all kinds of ailments”; “she had trouble falling
asleep even before starting school at age 6 and this was repeated over and
over until she got sick at age 13”; “since the 8th grade she tends to worry
and dwell on negatives.” Other examples of the raw data are shown in
quotations and case vignettes.
The Logs of the 3 raters were compared after completion of their
independent coding. In most instances, the Logs contained identical
citations from the medical records. When one rater noted something
not mentioned by another, the raters reexamined the citation page to
confirm or reject the questioned observation. Hence, a consensus was
obtained for all Logs. A code sheet was used to transfer the symptom/
behavior data from the Logs to a data entry format with 98 items on
the final coding list.
 SYMPTOM PATTERNS PRECEDING BIPOLAR ONSET

RESULTS regardless of gender, noted for 56% of males and 50% of

Data analyses were undertaken to generate hypotheses
about early prodromal features which could be tested in a
prospective study of children at familial, genetic risk for
BPI. All analyses were completed using SPSS (Version
9.0, 1998).
The frequency of the prodromal features most com-
monly reported by the family in the initial admission his-
tory for 58 subjects, later diagnosed with BPI, is shown
in Table 1. For the total sample, the symptoms/behaviors
with the highest frequency were depressed mood (53% of
the sample), increased energy (47%), decreased energy/
tired (38%), anger dyscontrol and/or quick temper and
argumentative (38%), and irritable mood (33%). The
next most commonly reported symptoms included
bold/intrusive behaviors, excessive behaviors, and con-
duct problems (28%–29%); decreased sleep and cried
(26%); and overly sensitive (24%). Informants specified
that certain symptoms/behaviors occurred episodically,
and no mention of recurrence was coded as unknown.
For the 7 top-ranked symptoms shown in Table 1, there
was evidence that most were highly episodic: depressed
mood, 24 (77%) of 31; increased energy, 21 (78%) of 27;
decreased energy/tired, 13 (59%) of 22; irritable mood,
15 (79%) of 19; and excessive behavior, 11 (69%) of 16.
A prominence of mood and energy symptoms is
repeated when gender is taken into account. The item
“depressed mood” remains the most cited symptom
females. Both sexes shared other key items such as
increased or decreased energy, being irritable, being bold
and demanding, and being overly sensitive. Significant
gender differences were found for several reported items,
and most of these were episodic. Compared with females,
males had more grandiosity (Fisher exact test: p = .001)
and excessive behavior (p = .003) and more lowered inhi-
bitions (p = .058). Females were more frequently cited as
crying (p = .000), having more obsessive-compulsive traits
(p = .035), and being more stubborn (p = .050).
There was a 9- to 12-year interval between the first
reported symptoms/behaviors and the onset of a major
affective disorder as defined by RDC, with no gender dif-
ferences. Since there were certain prodromal symptoms
that appeared earlier than others, the data were next
examined for only those symptoms/behaviors that
appeared from birth through age 15. The full sample of
58 was reduced to a sample of 40 patients with early signs
of illness. Because the focus of our interest was in pat-
terns of prodromal features in early childhood and ado-
lescence, the 18 patients who had symptoms only at older
ages were excluded. Age 15 was also defined as a cutoff
age to avoid coding behaviors that were possibly peer-
influenced examples of “sowing wild oats.” Young adoles-
cents are not part of a “courting group” until age 16, after
which they socialize away from home with a chosen
youth group, where behavioral influences are powerful.

TABLE 1
Symptoms and Behaviors Before Onset by Gender: Bipolar I Disorder Sample (N = 58; Males = 32, Females = 26)
Males Females Total
Symptoms/Behaviors No. % No. % No. %

Depressed mood 18 56 13 50 31 53
Increased energy 18 56 9 35 27 47
Decreased energy/tired 13 41 9 35 22 38
Anger dyscontrol/argumentative 14 44 9 35 23 38
Irritable mood 11 34 8 31 19 33
Bold/intrusive/demanding 9 28 8 31 17 29
Excessive behavior 14 44 2 8 16 28
Conduct problems 11 34 5 2 16 28
Decreased sleep 10 31 5 2 15 26
Cried 2 6 13 50 15 26
Overly sensitive 7 22 7 27 14 24
Guilt/self-reproach 9 28 4 15 13 22
Worried/anxious/fearful 4 12 9 35 13 22
Labile/mood changes 8 25 3 12 11 19
Somatic complaints 5 16 6 23 11 19
Grandiosity 10 31 0 0 10 17
Stubborn 1 3 6 23 7 12

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EGELAND ET AL.

Each of the 40 subjects had one or more early

23

23
23

15
38

27

15
35

23

19
15

15
%
signs/symptoms, and the age of occurrence had been

No.

6
6

4
10

4
9

5
4

4
coded. Table 2 shows the most frequently reported pro-

16 Males/10 Females
Ages 13–15 (n = 26)
dromal symptoms for 4 age categories: 0–6 years, 7–10
years, 11–12 years and 13–15 years. A given symptom for

Decreased energy/tired
a particular subject might have been reported at several

Symptom/Behavior

Guilt/self-reproach

Conduct problems
Anger dyscontrol
Bold/demanding
Depressed mood

Increased energy
ages and would appear in the count for each appropriate

Decreased sleep
Irritable mood

More talkative
age category. Hence the columns give counts for the ages

Withdrawn
at which the symptoms listed appeared. Each successive

Cried
age grouping included some children who appeared in
the previous age bracket, with a pattern of symptoms
emerging over a series of ages until onset of illness.

Most Frequently Noted Prodromal Features Before Onset by Age Categories for 40 Subjects
The 13 cases, aged 0–6, disclosed that 23% reported

30
50

30

30
30
30

30
%
“cried”; 23% had early periods of increased energy or were

No.
more active; and 23% were bold/demanding. Although

3
5

3
3
3

3
not seen in Table 2, it is noteworthy that 1 each of 29 dif-

Ages 11–12 (n = 10)

5 Males/5 Females
ferent symptoms/behaviors, almost all episodic in nature,

Worried/anxious/fearful
Decreased energy/tired
had been reported in this age 0–6 category. One female

Labile/mood changes

Cognition problems
Symptom/Behavior
patient’s record noted that “ever since she was a baby she

Depressed mood

Increased energy
had little sad spells” and by age 2 was a “nervous, problem
child” who had crying spells and somatic complaints and
was “sickly, run down and slowed down.” In one male’s

Cried
admission record, at age 15, his parents reported that by
TABLE 2

age 6, he had periods during which he was noticeably dif-

ferent from other boys with respect to the following:
“fussy” (i.e., cried more often), irritable moods, quick-
29

21
21

21
25

17
17

17
13
13
%

tempered, anger dyscontrol, conduct problems, and

No.

4
5

5
4
6

4
3
3
“being a terrible tease.” His parents told the social worker
12 Males/12 Females
Ages 7–10 (n = 24)

that from a very young age he was a “fight cat” and that
they could not leave him at home with his siblings.
Decreased energy/tired
Symptom/Behavior

These very early symptoms/behaviors are of increasing

Conduct problems
Bold/demanding
Overly sensitive

interest as one looks across the age categories that follow.

Irritable mood

Quick temper

The 7–10 age category had a proliferation in the number

Withdrawn
Shy/timid
Stubborn

of different prodromal features (n = 34) noted for both

Cried

boys and girls. The most frequent observation was irrita-

ble mood (29%), with all but one citation being recur-
rent in nature. “Overly sensitive” was reported in 25%.
As noted in Table 1, 24% of the total sample of 58 was
23
23
23
15

15
15
15
%

reported as “overly sensitive” at some age prior to their

No.

“RDC” onset. Parents or teachers who identify a young-

2

2
3
3

2
2

ster as overly sensitive refer to a child who has a height-

5 Males/8 Females
Ages 0–6 (n = 13)

ened sense of awareness. If one observes such children,

Worried/anxious/fearful

their “social skin” appears to be overexposed. They may

Cognition problems
Symptom/Behavior

seem “hyperalert” to the feelings of others—peers and

Bold/demanding
Increased energy

Quick temper

adults alike. It is as though an electrical field surrounds

Shy/timid

these youngsters and their antennae pick up all possible

signals. Other behavioral problems that were noticed by
Cried

parents and teachers in this age group are shown in Table

1248 J . A M . A C A D . C H I L D A D O L E S C . P S YC H I AT RY, 3 9 : 10 , O C TO B E R 2 0 0 0

2, namely, cried, bold/demanding, quick-tempered,
stubborn, and conduct problems. All represent depar-
tures from the normal role of Amish children at this age,
who are expected to be well-behaved, submissive to
authority, quiet, and nonintrusive around adults. Being
outspoken and bold in speech or behavior departs from
accepted norms for Amish of all ages.
Despite the small sample size (n = 10) for the 11–12 age
group, the scenario of mood changes and both phases of
energy was clearly evident. Depressed mood was the
most prevalent, seen in half the sample. Although there
were equal numbers by gender, only 27% of all reports
were for boys compared with 73% for girls. It is not
known whether or not menarche plays a part, inasmuch
as most Amish girls reach menarche by age 12 or 13.
Among the 13–15 age group, there was a total of 119
observations, 75% episodic, for 40 distinct antecedents.
Depressed mood still ranked first, occurring in 38% of
the 26 children, and was episodic in every instance except
one. Two primary symptoms for mania, decreased sleep
and increased talkativeness, began to appear in the counts,
evenly divided by gender. Evidence regarding bold behav-
iors, lack of impulse control, and various disciplinary
problems might now be interpreted with greater con-
fidence as representing the conventional “excessive behav-
ior” of a nascent manic illness.
While the data in Table 2 suggest a pattern of behaviors
throughout development, it is not clear whether there
might be an aggregation, or cluster, of prodromal features
within individuals that could be predictive of later onset of
bipolar illness. Our sample was too small to conduct
cluster analyses on these limited data. However, it is
important to note that the most commonly reported
symptoms/behaviors prior to age 16 for the sample of 40
cases parallel most of the top items shown in Table 1 for
the total sample. Among the most commonly reported
prodromal symptoms, there was a progression of average
ages of occurrence, beginning with “cried” (average age of
8.5) followed by overly sensitive, mood problems, quick
temper/anger dyscontrol, conduct problems, increased
energy, bold/demanding, decreased energy, and worried/
anxious. Three other important symptoms—depressed
mood, decreased sleep, and guilt/self reproach—appeared
on average between ages 13 and 15. It is interesting to note
that manic-type symptoms, like excessive behaviors and
grandiosity, tended to be manifest later in adolescence.
The following cases provide representative clinical nar-
ratives that illustrate some of these prodromal patterns.
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SYMPTOM PATTERNS PRECEDING BIPOLAR ONSET
The language quoted for these symptoms and behaviors
is typical of Amish descriptions of their children and is in
keeping with the current emphasis in psychiatry on the
importance of cultural competence. The names are pseu-
donyms, and sensitive materials were omitted to ensure
anonymity. Case 1 entered the study in 1976 (onset of ill-
ness dating earlier) and has been followed annually; case
2 was ascertained in 1982 and has been followed annually
since 1984; case 3 was ascertained in 1977 and has been
seen yearly since 1979.
Case Vignettes
Case 1: A Boy Who Alternated Between Quiet and Irri-
table. Joseph was a boy with typical growth and develop-
ment, but he suffered from early childhood illnesses
more than his 8 siblings. When Joe started school at age
6, his parents said he had already had definite periods of
being tired. Although usually considered a “jolly boy
who enjoyed himself,” the medical record showed that
there were other episodic symptoms including crying,
irritability, and depressed moods. His school perfor-
mance was sporadic; sometimes he was “extra good” and
at other times he “lost all interest.” Signs of a problem
were noticed again at age 11.
By the time Joe was 13, the family claimed that they
“could see it coming.” He began having alternating
periods of “quietness and irritability.” One moment he
would be in the playground ordering people around and
being too bossy; the next he would withdraw and sit
quietly inside, reading the Bible. For periods of a week
or so, Joe would sit around, tired, not talking and some-
times crying. During quiet times, he seemed “scared.”
He heard voices and talked about “strange things.”
There were rapid “extreme changes” when Joe would
“turn radical, wrecking stuff and tearing up” whatever his
siblings were playing with. Radical spells were character-
ized by overactivity, general restlessness, overtalkativeness,
and bold, loud, demanding, and hostile behavior with
many angry outbursts. These brief spells of being “quiet
versus irritable” persisted through ages 13 and 14. The
symptoms and cycling worsened dramatically at age 15,
when he was first admitted to a hospital. Joe’s illness then
met the full RDC for BPI. Currently in his 40s, he has
been hospitalized more than 50 times for a severe, rapid-
cycling bipolar disorder. He had long symptom-free
periods as a late adolescent, but his condition has deterio-
rated over time. The Amish Study continues to monitor
him for course-of-illness and seasonality research.
1249
EGELAND ET AL.
Case 2: A Girl Who Bossed Others and Was Fearful. The
best way to convey the pattern for Emma is to quote
directly from the coding sheet of prodromal symptoms,
all of which were reported as episodic in nature:
• Age 1: More active than normal. More demanding as
baby.
• Age 8: Bold/demanding/very outspoken.
• Age 10: Obsessive-compulsive traits (OCD). Mood
changes. Overly sensitive.
• Age 11: Irritable. Labile/mood changes. Depressed
mood.
• Age 12: Bold/intrusive/demanding/outspoken. OCD
and somatic traits.
At age 12 there were also nonepisodic symptoms:
energy loss, sleep unspecified, ruminations, fears/phobias,
panic symptoms, worried/fearful/tense.
Emma’s story begins sadly and ends on a more hopeful,
positive note. Emma was “a problem child from the start.”
She crawled everywhere and required much more atten-
tion than her siblings. She was called a “bold” child who
was self-centered and who “acted too adult.” By age 10,
she “bossed her younger sibs” and abdicated her work to
the older ones. Alternating moods, evident by age 10 or
11, were characterized as “moody and starey” versus “irri-
table and bossy.” Her parents said she was “changeable.”
Emma herself recalled having “weak periods” and a
problem expressing herself. She, like others, realized she
was “different and felt ashamed.” Her mother said she
worked harder in school for her grades than most but
“trailed along” and was only tolerated by the others.
“She always irked other children.” She was greedy, did
not share, and could not be trusted. During her child-
hood, Emma used rituals to “keep herself together” and
expressed a variety of fears (storms/dying). She was upset
easily, was very sensitive, and angered quickly. Over time
her moods intensified.
The onset of BPI was at age 16, when Emma was first
hospitalized with a mixed clinical picture of both euphoric
and irritable moods. After 3 months, she appeared
improved but was noncompliant with medications and
was readmitted twice in “stormy spells.” As she accepted
her illness and treatment, her world came into focus. For
the first 2 years of stability, Emma quilted at home and
then decided to teach Amish school, a stressful job in
which she was successful. She is doing very well, continues
to take medication, and has married.
Case 3: A School Girl Whose Problems Were Noticed by
Others. An average student in Amish school, Magdelena
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(Lena) was felt to be “a very sensitive child and perhaps
too shy.” Her teacher said she “got into upsets with the
other children” and spoke with the parents about the
girl’s tendency to be irritable at times. It was reported that
Lena could not play with the other children at school
because she wanted to have her own way and would not
cooperate. Periodically she seemed “too stubborn and
bold and talked too much.” Her usual manner was to be
quiet and shy.
At age 12, in the sixth grade, Lena herself was aware of
sleep difficulties for months. “I cried because I couldn’t
sleep.” A depressed mood was noted. By all accounts, she
was still shy, quiet, and overly sensitive.
Several episodic symptoms were again noted by age 13.
Lena was more talkative, fussy, outspoken, and bold
around others. At age 14, she was having more problems
of decreased sleep, mood changes, and crying. Full onset
was at age 16, when she became acutely manic and met all
conventional criteria. This episode persisted for 8 months
because formal medical treatment was not sought.
Even though Lena responds well to lithium and is
completely stable between episodes, the episodes have
occurred on average at 2-year intervals. Lena has a large
family, and some of her relapses have been associated
with pregnancy and stopping medication.
DISCUSSION
A symptom profile is emerging from the data presented
in this research that appears to be associated with early
prodromal features of BPI. It is revealing that the promi-
nence of mood and energy symptoms and sleep distur-
bance seen in our data correspond to the results of the
DMDA Study cited earlier (Lish et al., 1994). Whereas
that retrospective study depended on self-reports from
well-informed adult patients with BPI, our informants
had little if any prior experience with mental illness and
were speaking from an uninformed context. Therefore,
these 2 different sources of retrospective information pro-
vide evidence that mood changes, irritability/anger, and
the vegetative symptoms of energy and sleep are the most
frequently reported symptoms predating onset of BPI.
Limitations
There are several limitations to the present study. The
first is the small sample size (n = 58), which could lead to
some of our statistical findings being the result of ran-
dom variation. Replication of these findings in a larger

sample or in a prospective longitudinal sample is nec-
essary and should help resolve that question. Second,
there was no traditional control group for comparison to
subjects with other disorders. Hence, it is not yet pos-
sible to determine whether these symptoms and behav-
iors clearly distinguish the bipolar patient from the
unaffected person for whom comparable data would be
useful. However, parents and family reporting about
patients at first admission compared their behaviors with
that of unaffected siblings and peers in the Amish com-
munity as a contrast group. When they identified the
patient as the child who was or is “crying a lot,” “having
sleep problems,” “unruly,” or “overly sensitive,” the con-
trast was with those not showing these problems. Third,
retrospective data tend to be biased because of selective
recall and various other factors. Even though Amish
informants had little if any understanding of manic-
depressive disorder, common ideas regarding the nature
of mental illness would have influenced their insights
about early symptoms. Although there was no previous
episode of illness to bias the family informants at the
“onset” admission, it is possible that they were also
biased because of the nature of the current episode of ill-
ness. Finally, some of the “unspecified” symptoms/
behaviors had to be grouped for data entry and analysis.
One category involved “excessive behaviors,” including
observations such as “going overboard, chasing/pushing
other kids, being in a tear, fighting or being destructive.”
This required judgment decisions to define culturally
appropriate items for a given category.
Clinical Implications
Despite study limitations, our data provide testable
hypotheses that suggest specific symptoms may be relia-
ble indicators for the early detection of children at high-
est risk of developing BPI. If some of these symptoms/
behaviors are associated with subsequent onset of bipolar
disorder, they should be observed with increased frequency
among children at higher risk. Geller and Luby (1997)
state that “systematic research on pediatric BP is in its
infancy and will require ongoing and future studies to
provide developmentally relevant diagnostic methods
and treatment” (p. 1168). Prospective studies of the chil-
dren of a BPI parent would permit systematic collection
of data basic to developing a prodromal profile. We hope
to define more clearly which prodromal features are in-
volved in the ultimate manifestation of manic-depressive
disorder. To this end, the Amish Study, in 1994, launched
J . A M . A C A D . C H I L D A D O L E S C . P S YC H I AT RY, 3 9 : 10 , O C TO B E R 2 0 0 0
SYMPTOM PATTERNS PRECEDING BIPOLAR ONSET
a prospective investigation of children at high risk and
children from a matched sample of normal controls.
Continuing assessment of this sample of more than 200
children is done yearly using structured and semistruc-
tured interview instruments. Data analyses are being
conducted. Testing for symptoms and behaviors identi-
fied in this report represents a primary goal. Preliminary
results from analyses of first interviews appear consistent
with our hypothesis that certain symptoms may represent
a risk factor for developing bipolar disorder (Egeland and
Pauls, unpublished data, 1999).
The clinical implication of determining which pro-
dromal features could predict later illness is underscored
when one examines the average interval between the
emergence of the first affective-type symptoms and the
institution of treatment. In the present study, there was
an interval of 9 to 12 years, confirming our earlier report
of an average of 10 years (Egeland et al., 1987). This
suggests a possible earlier opportunity to initiate control
over emerging symptoms and to avoid the entrench-
ment of rapid cycling and increasing severity.
It is important that both prodromal features of the ill-
ness and actual criteria for pediatric bipolar disorder be
developed within the appropriate cultural context. The
definition of biological parameters seems simple com-
pared with defining appropriate criteria, in a cultural
context, for manic symptoms such as grandiosity and
the specifics of excessive behaviors that bring painful
consequences. Many of these behaviors are expressed
differently among Old Order Amish patients because
manic symptoms can be culture-bound. Strong religious
and community ties among the Amish do not give the
same messages, behavioral models, and opportunities as
those seen by researchers working with children from
other social, ethnic, or racial backgrounds. Hence, sensi-
tivity to symptoms and behaviors in a cultural context is
as important as defining them in appropriate age-graded
or developmental terms.
In summary, there are several points of clinical rel-
evance. We have identified a list of symptoms and behav-
iors that need to be replicated in prospective studies. We
hope that specific symptom constellations might predict
the at-risk child, even before a formal diagnosis could be
made. This effort would parallel research now being done
on prodromal features of schizophrenia. We have pro-
vided further evidence that early episodic mood and
energy symptoms/behaviors are perhaps at the core of the
emerging bipolar syndrome over an average interval of
1251
EGELAND ET AL.

10+ years. Defining the early symptoms that predate
onset of the full syndrome is a strategy that should lead to
earlier identification of children and adolescents who
would benefit from intervention of this recurrent and
severely debilitating condition.
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Prospective Evaluation of Mild to Moderate Pediatric Acetaminophen Exposures. Christy Rosa Mohler, MD, Sean P. Nordt,
PharmD, Saralyn R. Williams, MD, Anthony S. Manoguerra, PharmD, Richard F. Clark, MD
Study Objective: To determine whether pediatric patients with acute, mild to moderate acetaminophen exposures, treated with home
monitoring alone, develop systemic signs of hepatic injury. Methods: A prospective, observational study of calls to a regional poison
center over a 25-month period was performed. Patients were eligible for the study if they were younger than 7 years and had an acute
maximum possible acetaminophen exposure of up to 200 mg/kg. Exclusion criteria included previous decontamination measures, pos-
sibility of ingestion of an extended-release preparation, health or medication issues that could increase susceptibility to hepatotoxicity,
current symptoms of hepatotoxicity, and indeterminable ingestions. Study protocol included reviewing the signs and symptoms of
early and late acetaminophen toxicity, a 4- to 6-hour follow-up call, and a 72-hour follow-up call. Outcome measures were defined as
a verbal report by the patient’s parent or guardian of the presence or absence of signs or symptoms of hepatotoxicity. Results: A total of
1,039 patients were enrolled in the study, including 519 girls and 520 boys, with exposures ranging from 20 to 200 mg/kg. Eighteen
patients were lost to follow-up, data were incomplete for 2 patients. At 72-hour follow-up, the remaining 1,019 patients were all doing
well, without signs or symptoms of hepatotoxicity. Conclusion: On the basis of these data, pediatric patients with acute acetaminophen
exposures of up to 200 mg/kg, treated with home monitoring alone, do not develop signs or symptoms of hepatic injury. Ann Emerg
Med 2000;35:239–244. Reproduced with permission from Mosby-Year Book, Inc.

1252 J . A M . A C A D . C H I L D A D O L E S C . P S YC H I AT RY, 3 9 : 10 , O C TO B E R 2 0 0 0