Birmaher et al 2009; coby study

Am J Psychiatry 166:7, July 2009 795
Article
ajp.psychiatryonline.org
This article is featured in this month’s AJP Audio.
Four-Year Longitudinal Course of Children and
Adolescents With Bipolar Spectrum Disorders:
The Course and Outcome of Bipolar Youth (COBY) Study
Boris Birmaher, M.D.
David Axelson, M.D.
Benjamin Goldstein, M.D.
Michael Strober, Ph.D.
Mary Kay Gill, M.S.N.
Jeffrey Hunt, M.D.
Patricia Houck, M.S.H.
Wonho Ha, Ph.D.
Satish Iyengar, Ph.D.
Eunice Kim, Ph.D.
Shirley Yen, Ph.D.
Heather Hower, M.S.W.
Christianne Esposito-Smythers,
Ph.D.
Tina Goldstein, Ph.D.
Neal Ryan, M.D.
Martin Keller, M.D.
Objective: The authors sought to assess
the longitudinal course of youths with bi-
polar spectrum disorders over a 4-year
period.
Method: At total of 413 youths (ages 7–
17 years) with bipolar I disorder (N=244),
bipolar II disorder (N=28), and bipolar dis-
order not otherwise specified (N=141)
were enrolled in the study. Symptoms
were ascertained retrospectively on aver-
age every 9.4 months for 4 years using the
Longitudinal Interval Follow-Up Evalua-
tion. Rates and time to recovery and re-
currence and week-by-week symptomatic
status were analyzed.
Results: Approximately 2.5 years after
onset of their index episode, 81.5% of the
participants had fully recovered, but 1.5
years later 62.5% had a syndromal recur-
rence, particularly depression. One-third
of the participants had one syndromal re-
currence, and 30% had two or more. The
polarity of the index episode predicted
that of subsequent episodes. Participants
were symptomatic during 60% of the fol-
low-up period, particularly with subsyn-
dromal symptoms of depression and
mixed polarity, with numerous changes in
mood polarity. Manic symptomatology,
especially syndromal, was less frequent,
and bipolar II was mainly manifested by
depressive symptoms. Overall, 40% of the
participants had syndromal or subsyndro-
mal symptoms during 75% of the follow-
up period, and 16% of the participants ex-
perienced psychotic symptoms during
17% the follow-up period. Twenty-five
percent of youths with bipolar II con-
verted to bipolar I, and 38% of those with
bipolar disorder not otherwise specified
converted to bipolar I or II. Early onset, di-
agnosis of bipolar disorder not otherwise
specified, long illness duration, low socio-
economic status, and family history of
mood disorders were associated with
poorer outcomes.
Conclusions: Bipolar spectrum disorders
in youths are characterized by episodic ill-
ness with subsyndromal and, less fre-
quently, syndromal episodes with mainly
depressive and mixed symptoms and
rapid mood changes.
(Am J Psychiatry 2009; 166:795–804)
Prospective naturalistic studies of children and adoles-
cents with bipolar disorder (mainly subtype I) have shown
that while rates of recovery from index episodes are high,
in the range of 70%–100%, of those who recover, up to 80%
will experience one or more syndromal recurrences over a
period of 2 to 5 years (1–4). Moreover, prospective studies
have shown that, similar to findings reported for adults (1,
3, 4), youths with bipolar disorder experience frequent
mood fluctuations of varying intensities throughout 60%–
80% of the follow-up time, particularly depressive and
mixed symptoms.
Factors associated with worse longitudinal outcome in-
clude early age at illness onset, long illness duration,
mixed episodes, rapid cycling, psychosis, subsyndromal
symptoms, comorbid disorders, low socioeconomic sta-
tus, exposure to negative life events, lack of psychotherapy
treatment, poor adherence to pharmacological treatment,
and family psychopathology (1–6).
A prior study from the Course and Outcome of Bipolar
Youth (COBY) program that followed 263 youths with bi-
polar spectrum disorders for an average of 2 years showed
that during most of the follow-up time, youths experi-
enced subsyndromal and syndromal mood symptoms

796 Am J Psychiatry 166:7, July 2009
CHILDREN AND ADOLESCENTS WITH BIPOLAR SPECTRUM DISORDERS
and frequent mood fluctuations (4). Twenty percent of the
youths with bipolar II disorder converted to bipolar I dis-
order, and 25% of those with bipolar disorder not other-
wise specified converted to bipolar I or II disorder. The
aim of the present study was to extend COBY’s prior find-
ings in a larger sample of youths with bipolar spectrum
disorders followed for a longer time. For this purpose, the
data were evaluated with two complementary sets of anal-
yses. In the first, to compare our results with those of the
existing literature, we conducted analyses using survival
analytic techniques and the standard definitions of syn-
dromal recovery and recurrence. In the second, since pe-
diatric bipolar disorder is not manifested only by discrete
syndromal recurrences but also by numerous subsyndro-
mal episodes and mood changes, we conducted analyses
of the week-by-week mood symptoms over the follow-up
period. Subsequent reports will investigate how outcomes
are affected by other factors, such as subsyndromal recov-
eries, suicidal behaviors, health services utilization, psy-
chosocial functioning, exposure to negative life events,
specific comorbid disorders, and treatment.
Method
Participants
The methods for COBY have been described in detail elsewhere
(4, 7). Briefly, the study included youths ages 7 to 17 years 11
months with DSM-IV bipolar I or II disorder or operationally de-
fined bipolar disorder not otherwise specified. Youths with COBY-
defined bipolar disorder not otherwise specified were previously
shown to convert to bipolar I or II and to have a comparable but
less severe clinical picture, a similar family history, similar rates of
comorbid disorders, and a similar longitudinal outcome com-
pared with youths with bipolar I (4, 7).
Youths with schizophrenia, mental retardation, autism, and
mood disorders secondary to substances, medications, or medi-
cal conditions were excluded from the study.
Participants were recruited from outpatient clinics (67.6%), in-
patient units (14.3%), advertisements (13.3%), and referrals from
other physicians (4.8%). They were enrolled independent of cur-
rent mood state or treatment status.
The analyses in this study are based on the prospective evalua-
tion of 413 youths, including 244 (59.1%) with bipolar I disorder,
28 (6.8%) with bipolar II disorder, and 141 (34.1%) with bipolar
disorder not otherwise specified who had at least one follow-up
assessment. Participants had been prospectively interviewed ev-
ery 37.5 weeks (SD=20.8) for an average of 191.5 weeks (SD=75.7).
Youths with bipolar II were followed significantly longer (227.4
weeks [SD=76.6]) than those with the other two bipolar subtypes
(bipolar I: 183.2 weeks [SD=71.8]; bipolar disorder not otherwise
specified: 198.7 weeks [SD=79.8]; F=5.4, p=0.005).
At intake, participants with bipolar disorder not otherwise
specified were the youngest, followed by those with bipolar I and
then those with bipolar II (Table 1). More youths with bipolar dis-
order not otherwise specified were in Tanner stage I of sexual de-
velopment than those with bipolar II, and more youths with bi-
polar II were in Tanner stages IV or V than those with bipolar
disorder not otherwise specified. There were no between-group
differences in Tanner stages II or III. The mean age at onset of
mood symptoms was 8.4 years, and the mean age at onset of
DSM-IV mood episodes was 9.3 years (see below for the definition
of age at onset). The onset of mood symptoms and episodes was
significantly later in youths with bipolar II than in youths with the
other two bipolar subtypes. As expected, by definition, the polar-
ity of the index episode reflected the bipolar subtype, with mania
or hypomania being more common in youths with bipolar I than
in those with bipolar II or bipolar disorder not otherwise speci-
fied. However, youths with bipolar II had significantly more de-
pressive index episodes than youths with the other two subtypes.
Youths with bipolar I had more lifetime psychosis than those with
bipolar disorder not otherwise specified (for all above compari-
sons, p values were <0.05 and Cohen’s d ranged from 0.3 to 0.9).
There were no other significant between-group differences.
The retention rate was 86%, with 93% of participants complet-
ing at least one follow-up interview. Except for lower rates of anx-
iety disorders in youths who dropped out of the study (54.5%
compared with 38.7%; p=0.02), there were no other demographic
or clinical differences between those who continued in the study
and those who withdrew.
Procedures
Each participating university’s institutional review board ap-
proved the study, and consent was obtained from the participat-
ing youths and their parents. At intake, youths and parents were
directly interviewed for the presence of current and lifetime psy-
chiatric disorders in the youths. The instruments used were the
Schedule for Affective Disorders and Schizophrenia for School-
Age Children—Present and Lifetime Version (K-SADS-PL) (8), the
Kiddie Mania Rating Scale (K-MRS) (9), and the depression sec-
tion of the K-SADS-PL (10).
Longitudinal changes in psychiatric symptoms since the previ-
ous evaluation were assessed using the Longitudinal Interval Fol-
low-Up Evaluation (11) and tracked on a week-by-week basis us-
ing this instrument’s Psychiatric Status Rating Scales (12). These
scales use numeric values that have been operationally linked to
the DSM-IV criteria; DSM-IV criteria information is gathered in
the interview and then translated into ratings for each week of the
follow-up period. The ratings indicate the severity level of an epi-
sode as well as whether the patient has recovered or had a recur-
rence. For mood disorders, scores on the Psychiatric Status Rating
Scales range from 1 for no symptoms to 2–4 for varying levels of
subthreshold symptoms and impairment to 5–6 for meeting full
criteria with different degrees of severity or impairment. The con-
sensus scores obtained after interviewing parents and their chil-
dren were used for the analyses.
Family history of mood disorders was ascertained using the
Family History Screen (13). The Petersen Pubertal Development
Scale (14) and the equivalent Tanner stages were used to evaluate
and categorize pubertal stages. Socioeconomic status was ascer-
tained using the four-factor Hollingshead scale (15).
All assessments were conducted by research staff trained to reli-
ably administer the interviews; interview results were presented to
child psychiatrists or psychologists, who confirmed the diagnoses
and the Psychiatric Status Rating Scales scores. The overall K-
SADS-PL kappa coefficients for psychiatric disorders were ≥0.8.
The intraclass correlation coefficients for the K-MRS and the K-
SADS-P depression section were ≥0.95. The intraclass correlation
coefficients for syndromal and subsyndromal mood disorders as-
certained through the Psychiatric Status Rating Scales (using
methods described elsewhere [12]) were ≥0.75; the intraclass coef-
ficient correlations and the Kendall’s coefficients of concordance
were between 0.74 and 0.79 for a major depressive episode and be-
tween 0.60 and 0.67 for mania/hypomania.
During the follow-up, the K-MRS and the depression section of
the K-SADS-P were used as an additional assessment of mood
symptom severity for the week when symptoms were most severe
during the month prior to interview. A comparison of the maxi-
mum scores for depression and mania on the Psychiatric Status
Rating Scales for the 4 weeks prior to each follow-up assessment

BIRMAHER, AXELSON, GOLDSTEIN, ET AL.
and the maximum scores on the K-MRS and the depression sec-
tion of the K-SADS-P for the same period showed Spearman cor-
relations of 0.82 (p<0.0001) and 0.77 (p<0.0001), respectively.
Definitions of Clinical Course
Age at onset of bipolar disorder was defined as the age at onset
of a DSM-IV mood episode or an episode fulfilling the COBY’s
modified DSM-IV criteria for bipolar disorder not otherwise spec-
ified. The minimum age at onset was arbitrarily set at age 4. The
duration of bipolar disorder was calculated from the age at onset.
The index episode was defined as the current or most recent
DSM-IV mood episode.
The percentage of follow-up weeks spent asymptomatic or
symptomatic in the different mood symptom categories during
the entire follow-up period was computed for each participant,
based on Psychiatric Status Rating Scales scores. Full recovery
was defined as 8 consecutive weeks with a score ≤2 (minimal or
no mood symptoms) (4, 16). Time to recovery from the index epi-
sode was measured from the onset of the index episode. Partici-
pants were considered to have a recurrence (new episode) if they
had a Psychiatric Status Rating Scales score ≥5 with a duration of
1 week for mania/hypomania or 2 weeks for depression. Similar
to previous studies (16), “change in mood polarity” was defined as
a switch between depression (rating ≥3) and mania/hypomania
(rating ≥3) or vice versa with or without any intervening weeks
with no symptoms or when ratings for 1 week included both ma-
nia/hypomania and depression scores ≥3. This definition of
change in mood polarity is not the equivalent of DSM rapid cy-
cling. For rapid cycling as well as for mixed episodes, COBY used
the DSM-IV definitions.
Statistical Analyses
The syndromal recoveries and recurrences manifested in bipo-
lar disorder were evaluated using survival analyses and Cox pro-
portional hazards regressions (17). The numerous ongoing mood
changes and periods of subsyndromal symptoms of bipolar dis-
order were evaluated using within-group and between-group
analyses of the week-by-week syndromal and subsyndromal
symptoms, stratifying by bipolar subtype. Differences within and
between groups were analyzed using standard parametric and
nonparametric univariate tests.
TABLE 1. Demographic and Clinical Characteristics of 413 Youths With Bipolar Spectrum Disorders, by Bipolar Subtypea
Characteristic
Total Sample
(N=413)
Bipolar I
Disorder
(N=244)
Bipolar II
Disorder
(N=28)
Bipolar Disor-
der Not Other-
wise Specified
(N=141)
Analyses
Statistic df p
Mean SD Mean SD Mean SD Mean SD
Age 12.6 3.3 12.8a 3.2 14.8b 2.7 11.9c 3.2 F=11.0 2, 140 <0.001
Hollingshead Index of Social Status 3.4 1.2 3.4 1.3 3.8 0.9 3.4 1.1 Kruskal-Wallis
test=3.1
2 0.2
N % N % N % N %
Male 221 53.5 123 50.4 12 42.9 86 61.0 χ2=5.4 2 0.07
Caucasian 339 82.1 200 82.0 24 85.7 115 81.6 χ2=0.3 2 0.9
Living with both natural parents 174 42.1 94 38.5 17 60.7 6 44.7 χ2=5.6 2 0.06
Tanner stage of sexual development χ2=9.6 4 0.05
I 87 27.0 47 25.5a 2 7.4b 38 34.2a
II–III 89 27.6 50 27.2 8 29.6 31 27.9
IV–V 146 45.3 87 47.3a, b 17 63.0a 42 37.8b
Age at onset of mood symptoms
(years)
8.4 4.0 8.4a 4.3 10.5b 3.9 7.9a 3.4 Kruskal-Wallis
test=19.5
2 0.009
Duration of mood symptoms
(years)
4.4 3.0 4.5 3.1 4.3 2.6 4.2 2.9 F=0.4 2, 410 0.7
Age at onset of a DSM mood
episode (years)b
9.3 3.9 9.3a 4.1a 11.8b 3.2 8.7a 3.5 Kruskal-Wallis
test=4.5
2 0.001
Duration of bipolar disorder
(years)c
3.3 2.5 3.5 2.7 3.0 1.3 3.2 2.3 Kruskal-Wallis
test=0.5
2 0.8
N % N % N % N %
Polarity of index episode χ2=229.29 0.001
Depressed 58 14.0 34 7.0a 11 39.3b 13 9.2a
Hypomanic 34 8.2 17 13.9a 10 35.7b 7 5.0a
Manic 77 18.6 77 31.6a 0 0.0b 0 0.0b
Mixed 70 17.0 68 27.9a 0 0.0b 2 1.4b
Not otherwise specified 174 42.1 48 19.7a 7 25.0a 119 84.4b
Psychosis 92 22.3 69 28.3a 4 14.3a,b 19 13.5b χ2=12.4 2 0.002
Any comorbidity 351 85.0 206 84.4 22 78.6 123 87.2 Fisher’s exact
test
0.4
Family history
First-degree relative with mania
or hypomania
143 36.8 87 38.0 12 44.4 44 33.1 χ2=1.6 2 0.4
First-degree relative with depres-
sion
295 75.6 168 73.0 23 85.2 104 78.2 χ2=2.6 2 0.3
Second-degree relative with ma-
nia or hypomania
143 37.6 80 36.0 14 50.0 49 37.7 χ2=2.1 2 0.4
Second-degree relative with de-
pression
276 72.3 157 70.4 25 89.3 94 71.8 χ2=4.4 2 0.1
a Different subscripts indicate significant pairwise differences at p≤0.05.
b Age 4 is set as the minimum value.
c Calculated from age at onset of any DSM mood episode.

About 14% of the sample had their most recent mood episode
offset and recovered before intake. Since the analyses with and
without these participants yielded similar results, all participants
were included in the analyses.
The data were censored after participants with bipolar II and
bipolar disorder not otherwise specified converted to other bipo-
lar subtypes.
For all of these analyses, the effects of demographic variables,
age, bipolar subtype, psychosis, age at bipolar onset, duration of
bipolar disorder, presence of any comorbid disorder, and family
history of mood disorders, as well as interactions between these
variables, were evaluated. Variables were examined univariately,
and those that were significantly associated with the outcome of
interest were analyzed using multiple linear regressions. Analyz-
ing the data using generalized linear models yielded similar re-
sults. To assess the effects of age on outcome, the sample was di-
vided into three groups: children <12 years old, adolescents ≥12
years old with onset of their episodes prior to age 12, and adoles-
cents with onset of their episodes at or after age 12. Analyses in-
cluding age or pubertal status yielded similar results. Thus, only
the results including age are presented. Also, since bipolar sub-
type and polarity of the index bipolar episode were highly associ-
ated (φ=0.75, p≤0.0001) (also see Table 1), only the bipolar sub-
type was included in the analyses.
All p values are based on two-tailed tests with α set at 0.05.
Results
Survival Analyses
Recovery from the index episode. Overall, 81.4% of
the participants had full recovery, a median of 123.7 weeks
after the onset of the index episode (Table 2). Youths with
bipolar I showed significantly higher rates of recovery
compared to those with bipolar disorder not otherwise
specified, and those with bipolar I and II had shorter times
to recovery compared to those with bipolar disorder not
otherwise specified (Figure 1). In addition to the standard
8-week duration criterion for recovery, in analyses using 2,
4, and 6 weeks with minimal or no mood symptoms, rates
of recovery were 88%, 84%, and 81%, respectively.
A lower likelihood of full recovery was associated with a
diagnosis of bipolar disorder not otherwise specified (ver-
sus bipolar I and II, hazard ratio=0.62, 95% CI=0.49–0.97);
children with childhood onset (versus adolescents with
adolescent onset, hazard ratio=0.50, 95% CI=0.37–0.67;
versus adolescents with childhood onset, hazard ratio=
0.70, 95% CI=0.50–0.99); non-Caucasian race (hazard ra-
tio=0.60, 95% CI=0.42–0.84); longer duration of illness
(hazard ratio=0.83, 95% CI=0.78–0.88); and a family his-
tory of mania/hypomania in first- or second-degree rela-
tives (hazard ratio=0.79, 95% CI=0.63–0.99). Conversely,
the interaction of living with both biological parents and
having higher socioeconomic status was associated with a
greater likelihood of recovery (hazard ratio=1.23, 95% CI=
1.01–1.51). No other significant predictors or interactions
were found.
Recurrence after recovery from index episode. Of
the youths who recovered, 62.5% had a syndromal recur-
rence a median of 71 weeks after recovering from their
index episode (Table 2). Higher rates of, and shorter
times to, recurrence occurred among youths with bipo-
lar I and II as compared to those with bipolar disorder
not otherwise specified (Figure 2).
Participants who recovered had a mean of 1.1 syndromal
recurrences (SD=1.2) during the 4-year follow-up; 33%
(110/336) had one recurrence, 20% (66/336) had two recur-
rences, and 10% (34/336) had three or more recurrences
during the follow-up period. Across all bipolar subtypes,
most syndromal recurrences after the index episode were
major depressive episodes (59.5%), followed by hypomanic
(20.9%), manic (14.8%), and mixed (4.8%) episodes. Inter-
estingly, for youths whose index episode was a major de-
pression, a mixed episode, hypomania, or not otherwise
specified, 64% (109/171) of the first recurrences were major
depressions, followed by mania/hypomania (30%; 52/171)
and then mixed episodes (6%; 10/171). For youths whose
index episode was mania, the majority of first recurrences
were mania/hypomania (59%; 23/39), followed by depres-
sion (41%; 16/39). A subanalysis including only partici-
pants with bipolar I in an age band similar to that of a prior
bipolar I longitudinal study (3) yielded similar results.
An increased likelihood of recurrence was associated
with bipolar I and bipolar II (versus bipolar disorder not
otherwise specified, hazard ratio=1.37, 95% CI=1.01–1.88);
TABLE 2. Summary of Recovery and Recurrence in 413 Youths With Bipolar Spectrum Disorders, by Bipolar Subtypea
Total Sample Bipolar I Disorder Bipolar II Disorder
Bipolar Disorder
Not Otherwise
Specified
Analyses
Variable χ2 df p
N % N % N % N %
Rate of recovery 336/413 81.4 207/244a 84.8 21/28a,b 75.0 108/141b 76.6 4.80 2 0.09
Rate of recurrenceb 210/336 62.5 135/207a 65.2 17/21a 81.0 58/108b 53.7 7.27 2 0.03
Median Median Median Median
Time to recovery from the
index episode (weeks)c
123.7 78.3a 76.9a 180.0b 14.12 2 0.001
Time to recurrence (weeks)d 71.0 69.0a 45.0a 82.0b 7.73 2 0.02
b Recurrence required either 1 week of Psychiatric Status Rating Scales scores ≥5 for mania/hypomania or two consecutive weeks of Psychiatric
Status Rating Scales scores ≥5 for depression.
c The index episode was defined as the current or most recent episode from the data of intake. To ascertain the real duration of illness, time
to recovery was calculated from the onset of the index episode. Therefore, for some subjects the duration of episode exceeds the length of
prospective follow-up.
d Time to recurrence was calculated from the time participants fulfilled criteria for recovery until they met full criteria for a new episode.

lower socioeconomic status (hazard ratio=0.87, 95% CI=
0.77–0.97); and a family history of mania/hypomania in
first- or second-degree relatives (hazard ratio=1.38, 95%
CI=1.04–1.84). No other significant predictors or interac-
tions were found.
Week-by-Week Mood Analyses
Analyses for the entire sample. Overall, participants
spent approximately 40% of the time during the follow-up
period asymptomatic and 60% symptomatic (41.8% sub-
syndromal and 16.6% with syndromal symptomatology)
(Table 3). Participants spent significantly more time in
syndromal depression or mixed/cycling than in syndro-
mal mania/hypomania. There were no significant differ-
ences in time spent in each subsyndromal polarity.
Within-group analyses. Analyses within each bipolar
subtype showed that youths with bipolar I and bipolar dis-
order not otherwise specified spent significantly more fol-
low-up time with subsyndromal than with syndromal
symptoms. For youths with bipolar II, there was no differ-
ence in the proportion of follow-up time spent with syn-
dromal and subsyndromal symptoms. While experiencing
syndromal symptoms, all three bipolar subtypes spent
more time with depression and mixed/cycling symptoms
than with mania/hypomania. While experiencing subsyn-
dromal symptoms, youths with bipolar I spent more time
with subsyndromal mania and mixed symptoms than
with subsyndromal depression, and youths with bipolar
disorder not otherwise specified spent more time with
subsyndromal mixed symptoms than with the other two
subsyndromal polarities. For youths with bipolar II, there
were no significant differences in the amount of follow-up
time spent in each subsyndromal polarity. For all compar-
isons, p values were ≤0.05 and values for Cohen’s ds ranged
from 0.45 to 1.3.
Between-group analyses. Comparisons between bipo-
lar subtypes showed that youths with bipolar I spent more
follow-up time asymptomatic than did those with bipolar
disorder not otherwise specified. Youths with bipolar I and
II spent similar amounts of time with syndromal symp-
toms but more time than those with bipolar disorder not
otherwise specified. In contrast, youths with bipolar disor-
der not otherwise specified spent significantly more time
with subsyndromal symptoms than did those with the
other two bipolar subtypes. Within syndromal periods,
youths with bipolar I and II spent more time with hypo-
mania than did those with bipolar disorder not otherwise
specified, youths with bipolar II spent more time in major
depression episodes than did those with the other two bi-
polar subtypes, and youths with bipolar I spent more time
with mixed/cycling symptoms than did those with bipolar
disorder not otherwise specified. By definition, youths
with bipolar II and bipolar disorder not otherwise speci-
fied did not spend any weeks with syndromal mania or
mixed symptoms. Within subsyndromal periods, partici-
pants with bipolar I spent more weeks with subsyndromal
manic symptoms compared to those with bipolar II. For
all comparisons, p values were ≤0.05 and values for Co-
hen’s ds ranged from 0.24 to 0.63.
Multiple linear regression models. The following vari-
ables were associated with more follow-up weeks with any
mood symptoms: low socioeconomic status (t=4.28,
p<0.001), children with childhood onset (versus adoles-
cents with adolescent onset, t=5.07, p<0.001), adolescents
with childhood onset (versus adolescents with adolescent
onset, t=4.05, p<0.001), and presence of any comorbid dis-
order (t=2.62, p=0.009). No other significant predictors or
interactions were found. Except for bipolar I and II predict-
FIGURE 1. Survival Analysis of Recovery From Index Epi-
sode in Youths With Bipolar Disorder, by Bipolar Subtypea
a Log-rank χ2=14.01, p=0.0001. The index episode was defined as
the current or most recent syndromal DSM episode at intake. To as-
certain real duration of illness, time to recovery was calculated
from the onset of the index episode; therefore, for some youths,
the duration of the index episode exceeds the length of the pro-
spective follow-up period.
0.6
0.4
0.2
0.0
1.0
0.8
CumulativeProportionRecovered
4002000 600
Time to Recovery in Weeks
Bipolar I disorder (N=244)
Bipolar II disorder (N=28)
Bipolar disorder not
otherwise specified (N=141)
FIGURE 2. Survival Analysis of Recurrence After Recovery
From Index Episode of Bipolar Disorder, by Bipolar Subtypea
a Log-rank χ2=7.7, p=0.02. Time to recurrence was calculated from
the time youths fulfilled criteria for recovery until they met full cri-
teria for a new syndromal DSM mood episode.
0.6
0.4
0.2
0.0
1.0
0.8
CumulativeProportionRecurred
4003002001000
Time to Recurrence in Weeks
Bipolar I disorder (N=207)
Bipolar II disorder (N=21)
Bipolar disorder not
otherwise specified (N=108)

ing more follow-up time with syndromal symptomatology,
and bipolar disorder not otherwise specified and being
non-Caucasian predicting more time with subsyndromal
symptomatology, separate linear regressions for syndromal
and subsyndromal symptomatology yielded similar results.
Patients with chronic symptoms. In addition to ana-
lyzing the percentage of time participants spent symp-
tomatic (syndromal plus subsyndromal symptoms), we
calculated chronicity, as measured by the percentage of
participants who had syndromal and/or subsyndromal
mood symptoms ≥75% of the follow-up time. Approxi-
mately 38% of the participants, particularly those with bi-
polar I (bipolar I > bipolar disorder not otherwise speci-
fied, χ2=5.66, p=0.02), experienced chronic mood
symptoms, with only 3% of participants meeting full syn-
dromal criteria for mood episodes. Most of these chronic
symptoms were mixed (46%), followed by depression
(33.8%) and mania/hypomania (21%).
Psychosis. Clinically relevant psychotic symptoms were
defined as having a score of 3 (definitely present) for delu-
sions and/or hallucinations on the Psychiatric Status Rating
Scales. Overall, 16% of the participants experienced psy-
chotic symptoms during the follow-up period. For these
youths, psychotic symptoms were manifested during 17.1%
of the follow-up time. Participants with bipolar I spent sig-
nificantly more time with psychotic symptoms than did
those with bipolar disorder not otherwise specified.
Change in mood polarity. Shifts in mood polarity oc-
curred a mean of 36.2 times (SD=46.9) during the entire fol-
low-up period, or 12.1 times per year (SD=15.0) (Table 3). A
change in mood polarity once per year or less was ob-
served in 31.2% of the sample, five or more times per year
in 51.1%, 10 times or more per year in 38.7%, and more
than 20 times per year in 23.7%. Except for youths with bi-
polar disorder not otherwise specified being more likely to
have at least 10 changes in mood polarity per year com-
pared to those with either bipolar I or II (p values ≤0.03, val-
ues for Cohen’s ds ranging from 0.23 to 0.45), there were no
other between-group differences. In a multiple linear re-
gression, lower socioeconomic status (t=3.90, p=0.001),
children with childhood onset (versus adolescents with
adolescent onset, t=4.02, p=0.001), adolescents with child-
hood onset (versus adolescents with adolescent-onset, t=
3.73, p=0.001), and presence of any comorbid disorder (t=
2.04, p=0.04) were significant predictors of having a greater
number of changes in mood polarity per year. There were
no other significant predictors or interactions.
Conversion From Bipolar II to Bipolar I and
From Bipolar Disorder Not Otherwise Specified
to Bipolar I or II
Of the 169 youths with bipolar II and bipolar disorder
not otherwise specified, 61 (36.1%) converted to a differ-
ent bipolar subtype over the follow-up period. Of these,
25% (7/28) with bipolar II converted to bipolar I, 19.9%
(28/141) with bipolar disorder not otherwise specified
converted to bipolar I, and 18.4% (26/141) with bipolar
disorder not otherwise specified converted to bipolar II
(38.3% of youths with bipolar disorder not otherwise spec-
ified converted overall).
TABLE 3. Weekly Symptomatic Status and Changes in Mood Polarity in 413 Youths With Bipolar Spectrum Disorders, by
Bipolar Subtypea
Symptomatology
Total Sample
(N=413)
Bipolar I Disorder
(N=244)
Bipolar II Disorder
(N=28)
Bipolar Disorder
Not Otherwise
Specified (N=141)
Analyses
χ2 df p
Percentage of follow-up time
Asymptomatic 41.2 31.6 44.0a 30.6 45.0a,b 33.6 35.6b 32.4 8.08 2 0.02
Syndromal 16.6 21.9 17.8a 19.8 24.6a 28.0 12.8b 23.3 31.74 2 0.001
Mania 0.9 4.1 1.6a 5.3 0.0b 0.0 0.0b 0.0 61.49 2 0.001
Hypomania 1.8 6.1 2.7a 7.7 1.4a 2.7 0.3b 1.5 30.22 2 0.001
Mixed/cycling 7.9 16.1 8.1a 13.3 10.8a,b 22.1 7.0b 19.0 15.40 2 0.001
Major depressive disorder 6.0 13.1 5.5a 11.1 12.4b 19.4 5.5a 14.3 13.47 2 0.001
Subsyndromal 41.8 28.8 38.2a 25.4 30.4a 26.0 50.2b 32.8 16.24 2 0.001
Mania 14.1 18.9 14.1a 17.1 7.0b 10.9 15.6a,b 22.5 6.14 2 0.05
Mixed 15.4 22.2 13.2 18.6 8.9 16.5 20.6 27.4 4.78 2 0.09
Depression 12.2 16.9 10.9 14.2 14.5 21.2 14.1 20.0 0.41 2 0.8
Psychosis (delusions and/
or hallucinations)
3.1 12.9 3.4a 12.1 5.5a,b 20.5 2.3b 12.3 11.99 2 0.002
Number of changes in mood
polarity per yearb
12.1 15.0 11.0 13.8 10.3 16.3 14.3 16.7 2.46 2 0.3
N % N % N % N %
≤1 129 31.2 72 29.5 10 35.7 47 33.3 0.89 2 0.6
>5 211 51.1 123 50.4 10 35.7 78 55.3 3.70 2 0.2
>10 160 38.7 87 35.7a 7 25.0a 66 46.8b 7.07 2 0.03
>20 98 23.7 51 20.9 5 17.9 42 29.8 4.47 2 0.1
b Change in mood polarity indicates a switch between depression (Psychiatric Status Rating Scales score ≥3) and mania/hypomania (Psychiatric
Status Rating Scales score ≥3) or vice versa, with or without intervening weeks with asymptomatic status.

Discussion
Corroborating prior COBY findings (4), this study showed
that bipolar spectrum disorders in youths are episodic dis-
orders characterized most often by subsyndromal episodes
and less frequently by syndromal episodes, with mainly de-
pressive and mixed symptoms and rapid mood changes.
Survival analyses using the standard definitions of syn-
dromal recovery and recurrence (based on DSM-IV and
the literature) indicated that approximately 80% of youths
with bipolar spectrum disorders achieved full recovery
about 2.5 years after onset of their index episode. How-
ever, 1.5 years after full recovery, approximately 60% of the
participants had at least one syndromal recurrence. Com-
pared to youths with bipolar disorder not otherwise spec-
ified, those with bipolar I and II were more likely to recover
but also to have a less durable recovery.
During the entire follow-up period, one-third of the par-
ticipants had at least one syndromal recurrence and 30%
experienced more than two syndromal recurrences. Most
of these syndromal recurrences were major depressions,
followed by hypomanic, manic, and mixed episodes. In
general, the polarity of the index episode predicted the po-
larity of subsequent episodes.
In addition to the analyses focusing only on recovery
and recurrence of syndromal symptoms, week-by-week
analyses provided a more in-depth clinical picture of the
course of bipolar disorder, showing that distinct periods of
full syndromal mood episodes exist in youths with bipolar
spectrum disorders. However, these episodes are embed-
ded in more prevailing and longer periods of subsyndro-
mal mood symptomatology. Youths with bipolar spectrum
disorders were symptomatic during 60% of the follow-up
period, during which they spent about 2.5 times more
time with subsyndromal than with syndromal symptoma-
tology. Mixed/cycling and depressive symptoms ac-
counted for the greatest proportion of time ill. In contrast,
purely manic symptomatology, especially at the full syn-
dromal level, was less common. Rapid mood changes
were ubiquitous, and psychotic symptoms were relatively
common, particularly in youths with bipolar I. Chronic
symptoms, defined as having any type of symptoms dur-
ing 75% or more of the follow-up period, were present in
38% of the participants. Almost all of these chronic symp-
toms were subsyndromal and of the depressive type.
The week-by-week analyses also shed light on the simi-
larities and differences in the longitudinal patterns of
symptom phenomenology of youths with bipolar I and II
and bipolar disorder not otherwise specified. Bipolar I was
manifested by more time with subsyndromal than with
syndromal symptoms. Most of the syndromal time was
characterized by mixed/cycling or depressive symptoms,
and most of the subsyndromal time was with subsyndro-
mal manic or mixed symptoms. Youths with bipolar II
spent equal amounts of time in syndromal and subsyndro-
mal states. The syndromal episodes were most commonly
depression or mixed states, but there were no significant
differences in the proportion of time spent with any type of
subsyndromal symptoms. Finally, bipolar disorder not oth-
erwise specified was mainly manifested by periods of sub-
syndromal mixed symptoms, closely followed by periods of
subsyndromal manic or depressive symptoms.
Between-group comparisons provided preliminary vali-
dation for the subtyping of bipolar disorder in youths. In
general, in comparison with other subtypes, each bipolar
subtype continued to show some category-specific symp-
tomatology. For example, during follow-up, youths whose
initial diagnosis was bipolar I showed more syndromal,
mixed/rapid cycling, and manic/hypomanic symptoms
than did those with bipolar disorder not otherwise speci-
fied; youths with bipolar II spent more time in hypomania
than did those with bipolar disorder not otherwise speci-
fied and more time in depression than did those with bi-
polar I and bipolar disorder not otherwise specified; and
youths with bipolar disorder not otherwise specified spent
significantly more time with subsyndromal symptoms
than did those with bipolar I and II. However, there was
some symptom overlap among the different bipolar sub-
types, especially bipolar I and II. Moreover, 25% of youths
with bipolar II converted to bipolar I, and 38% of those
with bipolar disorder not otherwise specified converted to
bipolar I and II.
Although there were some differences in the demo-
graphic and clinical factors associated with the outcome
variables measured (recovery, time symptomatic, and
changes in polarity), in general, early onset of bipolar dis-
order, presence of comorbid disorders, family history of
mood disorders (particularly mania/hypomania), low so-
cioeconomic status, and non-Caucasian race were associ-
ated with worse outcome. Long duration of illness was also
associated with a lower likelihood of recovery, with each
year of illness decreasing the likelihood of recovery by 20%.
Before continuing the discussion of COBY’s findings, it
is important to note the limitations of this study. First, de-
spite efforts to obtain precise information, the data col-
lected through the Longitudinal Interval Follow-Up Evalu-
ation is subject to retrospective recall bias. Although it
appears that this instrument has adequate psychometric
properties (1, 4, 12), further studies using the methods de-
scribed by Warshaw et al. (12) and including blind inter-
viewers are warranted. Second, although COBY used the
standard definitions of course for recovery and recurrence
(1, 3, 18), the rates and duration of the mood episodes may
change according to the duration criteria and symptom
threshold severity chosen. Third, the results pertaining to
youths with bipolar II should be considered tentative
given the relatively small size of this group. However,
across all bipolar subtypes, after depression most syndro-
mal recurrences were hypomanias. Finally, as most partic-
ipants were Caucasian and were recruited primarily from
outpatient and, to a lesser extent, inpatient settings, the
generalizability of the observations to other populations

remains uncertain. Nevertheless, nonreferred adolescents
with bipolar disorder have been shown to have a similar
course and high morbidity (5).
Despite methodological differences, all existing studies
of the course of bipolar disorder in youths, regardless of
country and source of ascertainment, show that the likeli-
hood of recovery from the index episode is high (1–4).
However, as with adult populations, despite the high re-
covery rate, the rates of recurrence, persistence of subsyn-
dromal clinical morbidity, and rapid and frequent changes
in mood polarity are also high, and most syndromal and
subsyndromal recurrences are depressions (16, 19–23). It
does appear that the polarity of the index episode predicts
the polarity of the subsequent episodes (21, 24–28), which
suggests the possibility of using specific psychosocial and
pharmacological treatments based on the polarity of the
index episode.
The results of this and other emerging pediatric studies
suggest strong general similarities in the longitudinal
course of bipolar disorder in youths and adults, which is
mainly manifested by subsyndromal symptomatology
and rapid mood changes (1–4, 29). However, there is evi-
dence that very early onset confers greater liability for a
more chronic and fluctuating course, mixed/cycling epi-
sodes, high rates of comorbid disorders, and increased
rates of mood disorders in families (1, 3, 30–32). Converg-
ing with these accounts are reports indicating that adults
whose onset of bipolar disorder dates to childhood have a
more severe and chronic course, lower quality of life, and
more episodes, changes in mood polarity, suicidality, and
comorbidity (33–35).
Comparable with other findings in the literature (1–4, 6),
we found that childhood-onset bipolar disorder, comorbid
disorders, positive family history for mood disorders, and
low socioeconomic status were associated with poorer out-
come. Moreover, the probability of recovery was inversely
related to duration of illness, which further underscores
the importance of early detection of illness and rapid im-
plementation of stabilizing treatments. Such efforts may
be of even greater urgency for youths with bipolar disorder
who have risk factors associated with poorer outcome.
Similar to findings in the literature on major depression
(36), it appears that there are some differences in the fac-
tors associated with the various indices of clinical out-
come (recovery, recurrence, and amount of time symp-
tomatic). Moreover, as the polarity of the index episode
was shown to convey different prognostic characteristics,
it may be that these observations will be informative to
clinical practice. For example, since youths with depres-
sion were seen to have more depressive recurrences, they
may require more aggressive and specific therapies to re-
duce the risk of future depressive episodes.
To our knowledge, COBY is the first naturalistic, pro-
spective study of this affective subtype in youths—an im-
portant avenue of research given the modal age of onset of
bipolar II illness during adolescence (18, 27, 37). Consis-
tent with adult data on high levels of morbidity associated
with this subtype, youths with bipolar II had a greater
overall risk of recurrence and more depressive morbidity
compared to youths with bipolar I, and had rates of nonaf-
fective comorbidity, suicidality, nonsuicidal self-injurious
behaviors, functional impairment, and family history of
bipolar and other mood disorders comparable to those
with bipolar I (6, 7, 32, 38–40). Also, bipolar II in youths ap-
pears to be a far less stable phenotype than in adults; in
this cohort, 25% of the bipolar II youths converted to bipo-
lar I, a rate higher than that reported in adult studies (41).
Since this disorder is mainly characterized by episodes of
syndromal and subsyndromal depression across the
lifespan, it is well appreciated that periods of hypomania
can be misconstrued as normal fluctuations in mood or as
erratic behavior, and perhaps more so in adolescents (27,
42), resulting in a high risk of misclassification as recurrent
unipolar depression or other, nonaffective disorders.
Bipolar disorder not otherwise specified is character-
ized by rates of comorbidity, suicidality, functional impair-
ment (except hospitalizations), and family history of
mood disorders equivalent to those in youths with bipolar
I and II (6, 7, 32, 38–40). These findings, together with the
high rates of conversion to bipolar I or II, provide prelimi-
nary validation of its nosological affinity with bipolar I and
II disorder. It should be emphasized, however, that our
classification relied on the presence of an affective pheno-
type that differed from bipolar I or II due to failure to meet
the DSM-IV duration requirements for these subtypes.
Thus, our findings are in accord with studies in the adult
literature (18, 42, 43) emphasizing the existence of clini-
cally relevant episodes of mania/hypomania that last for
less time than required by DSM criteria. These episodes
are often overlooked because of the predominance of syn-
dromal depression and subsyndromal manic/mixed
symptoms of short duration in its expression. Results from
COBY suggest that bipolar disorder not otherwise speci-
fied is an episodic illness, albeit one that often comprises
subsyndromal episodes that should be considered distinct
from the symptomatology of youths with behavior disor-
ders and “severe mood dysregulation” (44).
In summary, although distinct episodes of full syndro-
mal mood symptomatology as well as durable periods of
euthymia can be identified in youths with bipolar disor-
der, the course of bipolar spectrum disorders in children
and adolescents is predominantly characterized by sub-
syndromal and, much less frequently, syndromal epi-
sodes. Rapid mood changes are evident during these epi-
sodes, which are mainly of depressive and mixed polarity.
During follow-up each bipolar subtype showed some dis-
tinct clinical characteristics and course, but there was
overlap in their symptoms and substantial conversion
from bipolar II and bipolar disorder not otherwise speci-
fied into other bipolar subtypes. The course of bipolar dis-
order, the relative infrequency of syndromal DSM manic
episodes, the effects of development in symptom manifes-

tation, and the high prevalence of comorbid disorders
may account, at least in part, for the difficulties in recog-
nizing and managing this illness in youths. The recur-
rence, chronicity, and psychosocial morbidity associated
with this illness in critical developmental stages call for its
prompt recognition and the development of more effica-
cious treatments, particularly since each year of illness ap-
pears to decrease the likelihood of recovery.
Received Oct. 23, 2008; revisions received Dec. 21, 2008, and Feb. 10,
2009; accepted Feb. 17, 2009 (doi: 10.1176/appi.ajp.2009.08101569).
From the Department of Psychiatry, Western Psychiatric Institute and
Clinic, University of Pittsburgh Medical Center, Pittsburgh; Department
of Psychiatry and Biobehavioral Sciences, David Geffen School of Med-
icine, University of California at Los Angeles; Department of Psychiatry
and Human Behavior, Warren Alpert Medical School, Brown University,
Providence, R.I.; Department of Statistics, University of Pittsburgh. Ad-
dress correspondence and reprint requests to Dr. Birmaher, Western
Psychiatric Institute and Clinic, 3811 O’Hara St., Pittsburgh, PA 15213;
birmaherb@upmc.edu (e-mail).
Dr. Birmaher has participated in forums sponsored by Forest, Shire,
Jazz Pharmaceuticals, Solvay, and Abcomm and receives royalties
from Random House and Lippincott Williams & Wilkins. Dr. Keller has
received research support from, served as consultant to, or served on
speakers bureaus or advisory boards for Abbott, Bristol-Myers
Squibb, CENEREX, Cephalon, Cypress Bioscience, Cyberonics, Forest,
Janssen, JDS, Medtronic, Neuronetics, Novartis, Organon, Pfizer,
Roche, Solvay, and Wyeth. All other authors report no competing in-
terests.
Supported by NIMH grants MH59929 (to Dr. Birmaher), MH59977
(to Dr. Strober), and MH59691 (to Dr. Keller).
The authors thank Carol Kostek for her assistance with manuscript
preparation and Shelli Avenevoli, Ph.D., at NIMH, for her support and
guidance.
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Birmaher et al 2009; coby study