--Janice Papolos and Demitri F. Papolos, M.D.
The preliminary findings of the
largest on-going study examining children at risk for bipolar disorder. Can
an early symptom profile be detected? The clinical features of hyper-alertness
and oversensitivity as early predictors of a bipolar disorder.
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In the spring issue of 2001, we
wrote a newsletter entitled What Can the Amish Teach Us About Early-Onset
Bipolar Disorder? It focused on a study of adult members of the Old Order
Amish in Lancaster, Pennsylvania who suffered with bipolar I disorder. At the
end of the newsletter we informed our readers that the principal authors of
the study, Dr. Janice Egeland and her colleagues, were conducting a long-term
study with 210 children (many who had a parent with bipolar I disorder). One
of the goals of the research was to determine if an early-symptom profile could
be detected before the onset of illness in the at-risk youngsters. We promised
we would interview Dr. Egeland again and report on her findings.
In July of 2003, the preliminary
results of the largest, most methodologically rigorous prospective study of
children at risk for bipolar disorder was published in the Journal of the
American Academy of Child & Adolescent Psychiatry. It is entitled “Prospective
Study of Prodromal Features for Bipolarity in Well Amish Children,” and
we think that this study is such a benchmark and that it archives such a treasure
trove of information that we wanted all of our readers to know about it.
Why the Amish Are a “Living
Laboratory” For Research In Bipolar Disorder
In many ways the Amish community
provides a natural laboratory for all genetic and clinical and phenomenological
research. It is a well-defined, closed population with little migration into
or out of the community. The community can trace its ancestry back to 30 progenitors
in Switzerland, and it maintains extensive genealogic records. The Amish community
encourages a high birth rate, so a researcher can study large families. It is
also important that this community prohibits the use of alcohol and drugs—substances
known to complicate prenatal health as well as diagnostic ascertainment and
assessment.
Finally, while the Amish have no
more bipolar disorder than any other population group, they have always viewed
bipolar disorder as a medical condition (“Siss im blut”—it’s
in the blood, as they say), and they seek medical care for what they view as
medical illnesses.
Dr. Egeland has been conducting
genetic and epidemiological studies among the Old Order Amish since 1976 and
has had a long-standing, trusting relationship with this community. Her earlier
studies have identified families with a high loading of bipolar I disorder under
genetic linkage study, and she can now look at the fourth and fifth generation
of children as she has known many of their parents since the parents were babies
themselves.
The Study Design and the Hypothesis
The Child and Adolescent Research
Evaluation (CARE) program of the Amish study was initiated in 1994 and was designed
to follow a group of 210 children and adolescents in two samples: a bipolar
I sample and a control sample. The bipolar I sample were the children of a parent
who was known to have bipolar I disorder. The control sample consisted of children
who had a well parent whose sibling had the disorder, and a group of children
with a family history negative for any psychiatric illness.
The hypothesis of the study was
that there would be a gradation of risk for bipolar disorder: with children
of one parent with the illness having the highest risk, followed by children
whose parents were well but had a sibling diagnosed with the disorder (nieces
and nephews), and by children in families with no history of the illness having
the lowest rating of risk.
If this hypothesis were correct,
the goal would be not only to gauge the genetic risk factors, but to identify
the temperamental features and behaviors that might be predictors of an eventual
manifestation of the illness.
At the time of recruitment in 1994,
14 candidate bipolar I families (8 fathers and 6 mothers with the illness) were
invited and agreed to participate. A matched control group was assembled with
children of same-sex psychiatrically-unaffected parents who had a sibling with
the illness. Because it was not possible to obtain a sibling control for all
the families, the parent with bipolar disorder was matched by sex, age, and
family size to an unrelated Amish man or woman with a family history that was
negative for psychiatric illness.
The final sample of 210 children
consisted of 100 children from 14 families where a mother or father had bipolar
I disorder; 77 children from 9 control families where the parents had a sibling
who had bipolar disorder; and 33 children from four control families with a
history negative for the illness.
How Was the Information About
the Children Collected?
In order to launch the study that
would follow children and adolescents over a twelve- to fifteen-year period,
Dr. Egeland and her colleagues and a group of child psychiatrists, child development
scientists, a pediatrician, and Amish advisors developed a formal schedule of
questions that became known as the CARE Interview. This interview covered medical
and developmental histories (Part A), a health narrative (Part B), and a third
questionnaire with 69 inquiries related to a wide range of symptoms and life
events (Part C). Part C’s questions were considered comprehensive enough
to reveal potential early or prodromal features of bipolar illness.
The parents were asked whether their
child was “noticeably different” from “other boys and girls”
his or her own age. In the Amish community there are such well-defined roles
for children, with specific chores expected at various ages that role performance
(and any possible impairment) can be detected quickly.
Amish children have no homework after
school. They go right home, go upstairs and change their clothes and go out
and do their chores. Therefore, if these chores are completed in an inconsistent
or spotty fashion, the parents realize that something is wrong. This is important
because “role impairment” (functioning) is an element in psychiatric
assessment. Hence, parental rating of chores gives a measure of “wellness”
for each child annually.
How the Children Were Evaluated
for Possible Risk
After a mother answered Part A of
the CARE Interview, both parents answered Parts B and C, and the narrative file
for each child was presented randomly to the CARE panel. This panel was composed
of two board-certified child psychiatrists, a board-certified general psychiatrist,
and a clinical psychologist.
All members of the panel were
totally blind to the children’s identity or family history.
The panel members independently
coded CARE narratives in sets of 10 children and recorded their clinical opinion
for risk of developing a bipolar disorder. The options the doctors had to code
these well children included high risk, moderate risk, low risk (these codes
indicated the highest risk ratings); well with a BP tag; or well with no evidence
of risk.
The“ BP tagged” risk
category was used for children who were well, but who were manifesting some
clinical features that suggested a possible onset of bipolar disorder in years
to come, but who did not at this time warrant a risk rating. Risk rating represented
a “clinical judgment” based on the substantial clinical experience
of the panel, and there had to be consensus about each rating.
Which Group of Symptoms Occurred
Most Frequently in Which Group of Children?
When all the data were assembled
and the statistical analyses performed, the children of a bipolar parent were
reported to have manifested more clinical features on the coding sheet than
the control group, and the children of well parents who were siblings of a bipolar
I patient manifested more clinical features than the children with no family
history of psychiatric illness.
To add in the statistics: When rated
for risk, 38% of the bipolar sample (compared to only 17% of the control sample)
had high-moderate-low -ratings. Yet the vast majority of children in the control
sample who had risk ratings, turned out to be the children who had an aunt or
uncle with the illness (83%).
Similar to other studies of genetic
risk, the children at highest risk had a parent with the illness. Children with
a second-degree relative had a reduced risk but this risk was still higher than
the risk for those who came from families negative for any psychiatric disorder.
Because we don’t want anyone
to misinterpret the statistics, it is important to point out that the 38% figure
is not the genetic risk factor to a child of a parent with bipolar. These Amish
children are well with certain symptoms/features, and--depending on how many
of the children onset with the illness--these symptoms/features may be suggestive
of an early symptom profile for bipolar disorder.
The genetic risk to a child of one
parent who has the illness is usually pegged between 20 and 30%. However, no
one knows which factors may forestall an illness from developing and which genes
might even be protective.
Which Clinical Features or Symptoms/Behaviors
Did the At-risk Children Have?
The children who had a parent with
bipolar I disorder had a statistically significant higher frequency for 10 clinical
features when compared to the control group. Listed alphabetically they are:
Anxious/worried
Attention poor/distractible in school
Energy low
Excited
Hyper-alert
Mood changes/labile
School role impairment
Sensitivity
Somatic complaints
Stubborn/determined
It is interesting that the temperamental
features of sensitivity, hyper-alertness, being anxious/worried or nervous appeared
to be continuous as the parents responded to these with remarks such as “always”
or “by nature.” However, half or more of the reports about decreased
or increased energy and mood were episodic and all but one report on anger/temper
showed as periodic rather than continuous.
This differs dramatically from the
ultra-ultra rapid-cycling pattern of mood, energy, irritability and temper problems
reported in so many non-Amish children, and raises questions about environmental
influences on the presentation of symptoms and course of illness.
The Temperamental Features of
Being Hyper-alert Or Overly Sensitive
Seventy percent of the children
at risk for bipolar disorder had parental reports mentioning how “hyper-alert”
and “overly sensitive” the children were. In the retrospective study
that Dr. Egeland reported on two years ago, one quarter of the adults with bipolar
I disorder had hospital records that noted “overly sensitive compared
to others” prior to onset. (That figure may have been higher, but these
were chart reviews of first hospitalizations and the symptom profile was not
probed systematically upon admission.)
Parents and teachers in the Amish
community who identify a child as “overly sensitive” refer to a
child who has a heightened sense of awareness. If one observes such children,
their “social skin” appears to be overexposed. They may seem “hyper-alert”
to the feelings of others—peers and adults alike. It is as though an electrical
field surrounds these youngsters and their antennae pick up all possible signals.
According to Dr. Egeland, “They
seem to notice everything: how someone is dressed, whether their shoes are shined…they
get very close to you and seem to need some physical contact. If another child
gets stung by a bee, this child will feel so deeply that she will cry for the
injured child.”
It has long been known that people
in a manic state are hyper-alert, hyper-vigilant, and hyper-sensitive. According
to the authors of the Amish findings, these features of being “overly
sensitive” and “hyper-alert” could be early predictors of
bipolarity.
Dr. Egeland then mentioned something
that struck us when she added: “These children feel things very intensely
and they are oversensitive to color.”
Parents who participated in the
original survey for The Bipolar Child also mentioned this overall sensitivity;
and one area of particular sensitivity was to color. One mother described her
young daughter as “very sensitive in the visual realm. She is drawn like
a magnet to some designs and colors, beautiful paintings, landscapes, and repelled
by others, as strongly as she reacts to odors and tastes.”
When one looks at the art of Peter
Paul Rubens, Vincent Van Gogh, Maurice Utrillo, Edvard Munch, and Jackson Pollack
(all of whom suffered with manic-depression) it is easy to see this important
sensitivity to color.
The Symptoms and Cycling Patterns
Of The At-Risk Amish Children In Contrast To Non-Amish Children
More severe symptoms and symptoms
of mania tend to manifest later in Amish children—most likely in adolescence.
In this population, symptoms were showing up in the prepubertal years, going
underground, and reemerging in adolescence. Also of interest, the Amish children
of a bipolar I parent were not at a higher risk for patterns of disruptive behaviors,
oppositional behaviors, or the hyperactivity so often seen in prepubertal children
diagnosed with the disorder in communities outside the Amish culture. The authors
write:
It is interesting that in our
prospective study, clinical features such as mood, increased and decreased
energy, decreased sleep, and anger/temper were noted to occur periodically
in 50% or more of the reports for children of a bipolar parent. Other studies
have suggested that the most frequent pattern of prodromal symptoms of bipolar
disorder is characterized by continuous and chronic manifestations of irritability,
mood dysregulation, and rapid cycling with little inter-episode relief.
What accounts for these differences
in presentation is not known, but it is interesting to speculate whether the
absence of alcoholism within the Amish community may differentially influence
the presentation of the illness in comparison with non-Amish families.
A Case Vignette
To demonstrate a possible prodromal
syndrome of one of the youngsters in the CARE Program, take a look at Rebecca’s
story:
Rebecca was born at home after
a long labor and was a fussy, colicky baby. Her infancy, growth and development
were normal. At age 6, she was reported to be bold, stubborn, overly attentive,
and slower to respond to discipline than her siblings. She was still “hyper-alert”
and sensitive when 10- to 11-years old and tended to want to know “everything
about everybody.” Becky was said to “worry like an adult about
grown up” things. By age 12, she had outgrown these traits and was a
good student. Other than headaches and feeling faint, nothing noteworthy was
reported for her early teens (ages 13 to14).
Three of the panel rated Becky
as well. One child psychiatrist rated her for low bipolar risk: “It
is difficult for me to rate her as outside the limits of ‘wellness’
but the combination of symptoms noted make me wonder; they seem to form a
‘mini-cluster.’” After group discussion, the consensus was
recorded as “well, with a BP tag.”
In the fall season after her 15th
birthday and our CARE update, Rebecca suffered a sudden “breakdown”
which lasted three months and required treatment. The updated information
was read and independently rated by the clinicians. Becky was moody and sad;
had significant weight loss, insomnia, loss of energy and interest, and self
reproach; could not focus and think clearly; and was fearful about dying and
delusional about death. The CARE panel agreed that she met standard diagnostic
criteria for a major depressive disorder. The clinicians upgraded the risk
rating from the original “well, with a BP tag,” to a “moderate”
risk rating for bipolar problems in the future. This decision was made blind
to pedigree identification and the fact that Rebecca’s father is a BPI
patient.
Relevant to this pattern was a
3 to4-year prospective study of predictors for those most likely to shift
from unipolar to bipolar disorder. Predictors, with high specificity for bipolar,
included a depressive cluster with rapid onset of symptoms, a family loading
for mood disorder and mood-congruent psychotic features. Becky fits this prediction.
Only time will tell whether or not
Becky will convert to the bipolar I form of the disorder, however, we should
keep in mind that Dr. Barbara Geller of Washington University in St. Louis reported
on a ten-year follow-up of a group of 72 children who were originally diagnosed
with depression before puberty (the average age at diagnosis was 10). By the
age of 20, nearly half--48%--had developed the bipolar form of the disorder.
Since children with ADHD were excluded from Dr. Geller’s study, it is
possible that these rates of switching would have been even higher.
It bears saying that antidepressants
should be used with utmost caution in children presenting with a syndrome that
seems to present so squarely in the depressive spectrum. All efforts toward
unearthing family history and any possible symptoms that may be temperamentally
in the bipolar spectrum should be examined repeatedly before consideration of
antidepressant treatment.
What Next?
According to Dr. Egeland and the
other authors of this article, the research in the CARE study now rests on the
ultimate outcome of a bipolar disorder diagnosis for a well child correctly
designated “at risk.” The researchers plan to follow the children
for 12 to15 years and will be reporting new findings in the literature throughout
that period of time. A new article is expected sometime next spring.
In the meantime, genetic markers
in one or more chromosomal regions for susceptibility gene(s) have been established
in adults with bipolar disorder in the Amish community, and the researchers
are collecting DNA from a number of the children in the CARE program. As this
program is the only prospective study with the goal of comparing clinical prediction
and genetic patterns for bipolar disorder, future reports from the Amish study
will no doubt do much to expand our knowledge of the genetics, the early symptoms,
and the course of childhood-onset bipolar disorder.
In Conclusion
Amish children live in a completely
pacifistic society where anger or violence are never displayed, and where they
are expected to be well-behaved, submissive to authority, quiet and non-intrusive
around adults. Their opinions are never asked for or expressed. These children
have never seen television, the nightly news or scary or gory movies, and they
have never played Nintendo. They use no electricity and tend to go to sleep
soon after nightfall and arise early with the sun—their sleep patterns
are extremely uniform. They also have many brothers and sisters who act as role
models, and are surrounded by cousins and peers who follow the traditions of
the community closely and thus provide an additional abundance of role models.
The social structure that surrounds children in this community is practically
impossible to duplicate.
And yet, Amish children who have
early symptoms of a possibly evolving illness cannot always conform to the expectations
of their culture—anymore than can children suffering with these symptoms
in the world outside.
- We’ll write again soon.
In the meantime, as always, we look forward to hearing from you. May the holidays
find harmony within your homes.
- Janice Papolos and Demitri
Papolos, M.D.
-
BIBLIOGRAPHY
Biederman, J., Mick, E., Faraone,
S. “Pediatric mania: a developmental subtype of bipolar disorder?" Biological Psychiatry 2002; 48:458-466.
Egeland, Janice A., Jon A Shaw,
Jean Endicott, et al. “Prospective study of prodromal features for bipolarity
in well Amish children.” Journal of the American Academy of Child &
Adolescent Psychiatry 2003; 42:786-796.
Egeland, JA, Hostetter AM, et al.
“Prodromal symptoms before onset of manic- depressive disorder suggested
by first hospital admission histories.” Journal of the American Academy
of Child & Adolescent Psychiatry 2000; 39:1245-1252.
Egeland, J. and Allen, C. Telephone
interviews of November 4 and 5, 2003.
Egeland, J. Email correspondence
of November 4, 2003.
Geller, B., Williams, M. “Prepubertal
and early adolescent bipolarity differentiate from ADHD by manic symptoms, grandiose
delusions, ultra-rapid or ultradian cycling.” Journal of Affective
Disorders 1998; 51:81-91.
Geller, B., Zimmerman, B., et al.
“Bipolar disorder at prospective follow-up of adults who had prepubertal
major depressive disorder.” American Journal of Psychiatry 2001;158:125-127.
Hershman, JD. and Lieb, J. Manic
Depression and Creativity. Amherst, NY: Prometheus Books, 1998.
Papolos, J. and D. “What can
the Amish teach us about early–onset bipolar disorder? “ The
Bipolar Child Newsletter January 2001, Vol. 6.
http://www.bipolarchild.com/newsletters/0101.html
Papolos, D. and J. The Bipolar
Child, Revised. New York: Broadway Books, 2002.
Strober, M. and Carlson GA. “Bipolar
illness in adolescents with major depression: clinical, genetic and psychopharmacologic
predictors in a three-four-year prospective follow-up investigation. Archives
of General Psychiatry 1982; 39: 549-555
The authors wish to thank Dr. Janice
Egeland and Mrs. Cleona Allen for their pioneering work in this field and for
their much-appreciated contributions to this newsletter, and a thank you as
well to Catherine Schwartz, Karen Williams, and Jeanne Langer.
ADDITIONAL NEWS:
The Juvenile Bipolar Research Foundation
(JBRF) is seeking families throughout the nation who have two or more children
diagnosed with early-onset bipolar disorder for an affected sib pair genetic
study. To learn more about this study, please email Janice Papolos at jpapolos@jbrf.org.
For readers who have asked when
Demitri Papolos will be speaking in their area, save January 24th in Colorado
Springs, and February 21st in Ashville, North Carolina. For more details and
contact information go to http://www.bipolarchild.com/tour.html.
www.bipolarchild.com
