The study followed 413 youths with bipolar spectrum disorders for an average of 4 years. Key findings include: 1) About 80% recovered from their initial episode within 2.5 years, but recurrence rates were high, with 62.5% experiencing a new episode 1.5 years later, mainly depression. 2) Participants experienced mood symptoms for 60% of the follow-up period, particularly subthreshold depression and mixed states, with frequent changes in polarity. 3) Worse longitudinal outcomes were associated with early onset, diagnosis of bipolar disorder not otherwise specified, long illness duration, low socioeconomic status, and family history of mood disorders.

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

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

3. BIRMAHER, AXELSON, GOLDSTEIN, ET AL.
TABLE 1. Demographic and Clinical Characteristics of 413 Youths With Bipolar Spectrum Disorders, by Bipolar Subtype a
Bipolar Disor- Analyses
Bipolar I Bipolar II der Not Other-
Total Sample Disorder Disorder wise Specified
Characteristic (N=413) (N=244) (N=28) (N=141) 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 2 0.2
test=3.1
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
Mean SD Mean SD Mean SD Mean SD
Age at onset of mood symptoms 8.4 4.0 8.4a 4.3 10.5b 3.9 7.9a 3.4 Kruskal-Wallis 2 0.009
(years) test=19.5
Duration of mood symptoms 4.4 3.0 4.5 3.1 4.3 2.6 4.2 2.9 F=0.4 2, 410 0.7
(years)
Age at onset of a DSM mood 9.3 3.9 9.3a 4.1a 11.8b 3.2 8.7a 3.5 Kruskal-Wallis 2 0.001
episode (years)b test=4.5
Duration of bipolar disorder 3.3 2.5 3.5 2.7 3.0 1.3 3.2 2.3 Kruskal-Wallis 2 0.8
(years)c test=0.5
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 0.4
test
Family history
First-degree relative with mania 143 36.8 87 38.0 12 44.4 44 33.1 χ2=1.6 2 0.4
or hypomania
First-degree relative with depres- 295 75.6 168 73.0 23 85.2 104 78.2 χ2=2.6 2 0.3
sion
Second-degree relative with ma- 143 37.6 80 36.0 14 50.0 49 37.7 χ2=2.1 2 0.4
nia or hypomania
Second-degree relative with de- 276 72.3 157 70.4 25 89.3 94 71.8 χ2=4.4 2 0.1
pression
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.
and the maximum scores on the K-MRS and the depression sec- 1 week for mania/hypomania or 2 weeks for depression. Similar
tion of the K-SADS-P for the same period showed Spearman cor- to previous studies (16), “change in mood polarity” was defined as
relations of 0.82 (p<0.0001) and 0.77 (p<0.0001), respectively. a switch between depression (rating ≥3) and mania/hypomania
(rating ≥3) or vice versa with or without any intervening weeks
Definitions of Clinical Course with no symptoms or when ratings for 1 week included both ma-
Age at onset of bipolar disorder was defined as the age at onset nia/hypomania and depression scores ≥ 3. This definition of
of a DSM-IV mood episode or an episode fulfilling the COBY’s change in mood polarity is not the equivalent of DSM rapid cy-
modified DSM-IV criteria for bipolar disorder not otherwise spec- cling. For rapid cycling as well as for mixed episodes, COBY used
ified. The minimum age at onset was arbitrarily set at age 4. The the DSM-IV definitions.
duration of bipolar disorder was calculated from the age at onset.
The index episode was defined as the current or most recent Statistical Analyses
DSM-IV mood episode.
The syndromal recoveries and recurrences manifested in bipo-
The percentage of follow-up weeks spent asymptomatic or
lar disorder were evaluated using survival analyses and Cox pro-
symptomatic in the different mood symptom categories during
the entire follow-up period was computed for each participant, portional hazards regressions (17). The numerous ongoing mood
based on Psychiatric Status Rating Scales scores. Full recovery changes and periods of subsyndromal symptoms of bipolar dis-
was defined as 8 consecutive weeks with a score ≤2 (minimal or order were evaluated using within-group and between-group
no mood symptoms) (4, 16). Time to recovery from the index epi- analyses of the week-by-week syndromal and subsyndromal
sode was measured from the onset of the index episode. Partici- symptoms, stratifying by bipolar subtype. Differences within and
pants were considered to have a recurrence (new episode) if they between groups were analyzed using standard parametric and
had a Psychiatric Status Rating Scales score ≥5 with a duration of nonparametric univariate tests.
Am J Psychiatry 166:7, July 2009 ajp.psychiatryonline.org 797

4. CHILDREN AND ADOLESCENTS WITH BIPOLAR SPECTRUM DISORDERS
TABLE 2. Summary of Recovery and Recurrence in 413 Youths With Bipolar Spectrum Disorders, by Bipolar Subtype a
Bipolar Disorder Analyses
Not Otherwise
Variable Total Sample Bipolar I Disorder Bipolar II Disorder Specified 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 123.7 78.3a 76.9a 180.0b 14.12 2 0.001
index episode (weeks)c
Time to recurrence (weeks)d 71.0 69.0a 45.0a 82.0b 7.73 2 0.02
a Different subscripts indicate significant pairwise differences at p≤0.05.
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.
About 14% of the sample had their most recent mood episode adolescent onset, hazard ratio=0.50, 95% CI=0.37–0.67;
offset and recovered before intake. Since the analyses with and versus adolescents with childhood onset, hazard ratio=
without these participants yielded similar results, all participants
0.70, 95% CI=0.50–0.99); non-Caucasian race (hazard ra-
were included in the analyses.
tio=0.60, 95% CI=0.42–0.84); longer duration of illness
The data were censored after participants with bipolar II and
bipolar disorder not otherwise specified converted to other bipo- (hazard ratio=0.83, 95% CI=0.78–0.88); and a family his-
lar subtypes. tory of mania/hypomania in first- or second-degree rela-
For all of these analyses, the effects of demographic variables, tives (hazard ratio=0.79, 95% CI=0.63–0.99). Conversely,
age, bipolar subtype, psychosis, age at bipolar onset, duration of the interaction of living with both biological parents and
bipolar disorder, presence of any comorbid disorder, and family having higher socioeconomic status was associated with a
history of mood disorders, as well as interactions between these
variables, were evaluated. Variables were examined univariately,
greater likelihood of recovery (hazard ratio=1.23, 95% CI=
and those that were significantly associated with the outcome of 1.01–1.51). No other significant predictors or interactions
interest were analyzed using multiple linear regressions. Analyz- were found.
ing the data using generalized linear models yielded similar re-
sults. To assess the effects of age on outcome, the sample was di- Recurrence after recovery from index episode. O f
vided into three groups: children <12 years old, adolescents ≥12 the youths who recovered, 62.5% had a syndromal recur-
years old with onset of their episodes prior to age 12, and adoles- rence a median of 71 weeks after recovering from their
cents with onset of their episodes at or after age 12. Analyses in- index episode (Table 2). Higher rates of, and shorter
cluding age or pubertal status yielded similar results. Thus, only
times to, recurrence occurred among youths with bipo-
the results including age are presented. Also, since bipolar sub-
type and polarity of the index bipolar episode were highly associ- lar I and II as compared to those with bipolar disorder
ated (φ=0.75, p≤0.0001) (also see Table 1), only the bipolar sub- not otherwise specified (Figure 2).
type was included in the analyses. Participants who recovered had a mean of 1.1 syndromal
All p values are based on two-tailed tests with α set at 0.05. recurrences (SD=1.2) during the 4-year follow-up; 33%
(110/336) had one recurrence, 20% (66/336) had two recur-
Results rences, and 10% (34/336) had three or more recurrences
during the follow-up period. Across all bipolar subtypes,
Survival Analyses most syndromal recurrences after the index episode were
Recovery from the index episode. Overall, 81.4% of major depressive episodes (59.5%), followed by hypomanic
the participants had full recovery, a median of 123.7 weeks (20.9%), manic (14.8%), and mixed (4.8%) episodes. Inter-
after the onset of the index episode (Table 2). Youths with estingly, for youths whose index episode was a major de-
bipolar I showed significantly higher rates of recovery pression, a mixed episode, hypomania, or not otherwise
compared to those with bipolar disorder not otherwise specified, 64% (109/171) of the first recurrences were major
specified, and those with bipolar I and II had shorter times depressions, followed by mania/hypomania (30%; 52/171)
to recovery compared to those with bipolar disorder not and then mixed episodes (6%; 10/171). For youths whose
otherwise specified (Figure 1). In addition to the standard index episode was mania, the majority of first recurrences
8-week duration criterion for recovery, in analyses using 2, were mania/hypomania (59%; 23/39), followed by depres-
4, and 6 weeks with minimal or no mood symptoms, rates sion (41%; 16/39). A subanalysis including only partici-
of recovery were 88%, 84%, and 81%, respectively. pants with bipolar I in an age band similar to that of a prior
A lower likelihood of full recovery was associated with a bipolar I longitudinal study (3) yielded similar results.
diagnosis of bipolar disorder not otherwise specified (ver- An increased likelihood of recurrence was associated
sus bipolar I and II, hazard ratio=0.62, 95% CI=0.49–0.97); with bipolar I and bipolar II (versus bipolar disorder not
children with childhood onset (versus adolescents with otherwise specified, hazard ratio=1.37, 95% CI=1.01–1.88);
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5. BIRMAHER, AXELSON, GOLDSTEIN, ET AL.
FIGURE 1. Survival Analysis of Recovery From Index Epi- FIGURE 2. Survival Analysis of Recurrence After Recovery
sode in Youths With Bipolar Disorder, by Bipolar Subtypea From Index Episode of Bipolar Disorder, by Bipolar Subtypea
1.0 1.0
Cumulative Proportion Recovered
Cumulative Proportion Recurred
0.8 0.8
0.6 0.6
0.4 Bipolar I disorder (N=244) 0.4 Bipolar I disorder (N=207)
Bipolar II disorder (N=28) Bipolar II disorder (N=21)
0.2 Bipolar disorder not 0.2 Bipolar disorder not
otherwise specified (N=141) otherwise specified (N=108)
0.0 0.0
0 200 400 600 0 100 200 300 400
Time to Recovery in Weeks Time to Recurrence in Weeks
a Log-rank χ2=14.01,
p=0.0001. The index episode was defined as a Log-rank χ2=7.7, p=0.02. Time to recurrence was calculated from
the current or most recent syndromal DSM episode at intake. To as- the time youths fulfilled criteria for recovery until they met full cri-
certain real duration of illness, time to recovery was calculated teria for a new syndromal DSM mood episode.
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. isons, p values were ≤0.05 and values for Cohen’s ds ranged
from 0.45 to 1.3.
lower socioeconomic status (hazard ratio=0.87, 95% CI= Between-group analyses. Comparisons between bipo-
0.77–0.97); and a family history of mania/hypomania in lar subtypes showed that youths with bipolar I spent more
first- or second-degree relatives (hazard ratio=1.38, 95% follow-up time asymptomatic than did those with bipolar
CI=1.04–1.84). No other significant predictors or interac- disorder not otherwise specified. Youths with bipolar I and
tions were found. II spent similar amounts of time with syndromal symp-
toms but more time than those with bipolar disorder not
Week-by-Week Mood Analyses
otherwise specified. In contrast, youths with bipolar disor-
Analyses for the entire sample. Overall, participants der not otherwise specified spent significantly more time
spent approximately 40% of the time during the follow-up with subsyndromal symptoms than did those with the
period asymptomatic and 60% symptomatic (41.8% sub- other two bipolar subtypes. Within syndromal periods,
syndromal and 16.6% with syndromal symptomatology) youths with bipolar I and II spent more time with hypo-
(Table 3). Participants spent significantly more time in mania than did those with bipolar disorder not otherwise
syndromal depression or mixed/cycling than in syndro- specified, youths with bipolar II spent more time in major
mal mania/hypomania. There were no significant differ- depression episodes than did those with the other two bi-
ences in time spent in each subsyndromal polarity. polar subtypes, and youths with bipolar I spent more time
Within-group analyses. Analyses within each bipolar with mixed/cycling symptoms than did those with bipolar
subtype showed that youths with bipolar I and bipolar dis- disorder not otherwise specified. By definition, youths
order not otherwise specified spent significantly more fol- with bipolar II and bipolar disorder not otherwise speci-
low-up time with subsyndromal than with syndromal fied did not spend any weeks with syndromal mania or
symptoms. For youths with bipolar II, there was no differ- mixed symptoms. Within subsyndromal periods, partici-
ence in the proportion of follow-up time spent with syn- pants with bipolar I spent more weeks with subsyndromal
dromal and subsyndromal symptoms. While experiencing manic symptoms compared to those with bipolar II. For
syndromal symptoms, all three bipolar subtypes spent all comparisons, p values were ≤0.05 and values for Co-
more time with depression and mixed/cycling symptoms hen’s ds ranged from 0.24 to 0.63.
than with mania/hypomania. While experiencing subsyn- Multiple linear regression models. The following vari-
dromal symptoms, youths with bipolar I spent more time ables were associated with more follow-up weeks with any
with subsyndromal mania and mixed symptoms than mood symptoms: low socioeconomic status (t=4.28,
with subsyndromal depression, and youths with bipolar p<0.001), children with childhood onset (versus adoles-
disorder not otherwise specified spent more time with cents with adolescent onset, t=5.07, p<0.001), adolescents
subsyndromal mixed symptoms than with the other two with childhood onset (versus adolescents with adolescent
subsyndromal polarities. For youths with bipolar II, there onset, t=4.05, p<0.001), and presence of any comorbid dis-
were no significant differences in the amount of follow-up order (t=2.62, p=0.009). No other significant predictors or
time spent in each subsyndromal polarity. For all compar- interactions were found. Except for bipolar I and II predict-
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6. CHILDREN AND ADOLESCENTS WITH BIPOLAR SPECTRUM DISORDERS
TABLE 3. Weekly Symptomatic Status and Changes in Mood Polarity in 413 Youths With Bipolar Spectrum Disorders, by
Bipolar Subtypea
Bipolar Disorder Analyses
Total Sample Bipolar I Disorder Bipolar II Disorder Not Otherwise
Symptomatology (N=413) (N=244) (N=28) Specified (N=141) χ2 df p
Mean SD Mean SD Mean SD Mean SD
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/ 3.1 12.9 3.4a 12.1 5.5a,b 20.5 2.3b 12.3 11.99 2 0.002
or hallucinations)
Number of changes in mood 12.1 15.0 11.0 13.8 10.3 16.3 14.3 16.7 2.46 2 0.3
polarity per yearb
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
a Different subscripts indicate significant pairwise differences at p≤0.05.
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.
ing more follow-up time with syndromal symptomatology, change in mood polarity once per year or less was ob-
and bipolar disorder not otherwise specified and being served in 31.2% of the sample, five or more times per year
non-Caucasian predicting more time with subsyndromal in 51.1%, 10 times or more per year in 38.7%, and more
symptomatology, separate linear regressions for syndromal than 20 times per year in 23.7%. Except for youths with bi-
and subsyndromal symptomatology yielded similar results. polar disorder not otherwise specified being more likely to
Patients with chronic symptoms. In addition to ana- have at least 10 changes in mood polarity per year com-
lyzing the percentage of time participants spent symp- pared to those with either bipolar I or II (p values ≤0.03, val-
tomatic (syndromal plus subsyndromal symptoms), we ues for Cohen’s ds ranging from 0.23 to 0.45), there were no
calculated chronicity, as measured by the percentage of other between-group differences. In a multiple linear re-
participants who had syndromal and/or subsyndromal gression, lower socioeconomic status (t=3.90, p=0.001),
mood symptoms ≥75% of the follow-up time. Approxi- children with childhood onset (versus adolescents with
mately 38% of the participants, particularly those with bi- adolescent onset, t=4.02, p=0.001), adolescents with child-
polar I (bipolar I > bipolar disorder not otherwise speci- hood onset (versus adolescents with adolescent-onset, t=
fied, χ 2 =5.66, p=0.02), experienced chronic mood 3.73, p=0.001), and presence of any comorbid disorder (t=
symptoms, with only 3% of participants meeting full syn- 2.04, p=0.04) were significant predictors of having a greater
dromal criteria for mood episodes. Most of these chronic number of changes in mood polarity per year. There were
symptoms were mixed (46%), followed by depression no other significant predictors or interactions.
(33.8%) and mania/hypomania (21%).
Psychosis. Clinically relevant psychotic symptoms were
Conversion From Bipolar II to Bipolar I and
defined as having a score of 3 (definitely present) for delu- From Bipolar Disorder Not Otherwise Specified
sions and/or hallucinations on the Psychiatric Status Rating to Bipolar I or II
Scales. Overall, 16% of the participants experienced psy- Of the 169 youths with bipolar II and bipolar disorder
chotic symptoms during the follow-up period. For these not otherwise specified, 61 (36.1%) converted to a differ-
youths, psychotic symptoms were manifested during 17.1% ent bipolar subtype over the follow-up period. Of these,
of the follow-up time. Participants with bipolar I spent sig- 25% (7/28) with bipolar II converted to bipolar I, 19.9%
nificantly more time with psychotic symptoms than did (28/141) with bipolar disorder not otherwise specified
those with bipolar disorder not otherwise specified. converted to bipolar I, and 18.4% (26/141) with bipolar
Change in mood polarity. Shifts in mood polarity oc- disorder not otherwise specified converted to bipolar II
curred a mean of 36.2 times (SD=46.9) during the entire fol- (38.3% of youths with bipolar disorder not otherwise spec-
low-up period, or 12.1 times per year (SD=15.0) (Table 3). A ified converted overall).
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7. BIRMAHER, AXELSON, GOLDSTEIN, ET AL.
Discussion depression or mixed states, but there were no significant
differences in the proportion of time spent with any type of
Corroborating prior COBY findings (4), this study showed subsyndromal symptoms. Finally, bipolar disorder not oth-
that bipolar spectrum disorders in youths are episodic dis- erwise specified was mainly manifested by periods of sub-
orders characterized most often by subsyndromal episodes syndromal mixed symptoms, closely followed by periods of
and less frequently by syndromal episodes, with mainly de- subsyndromal manic or depressive symptoms.
pressive and mixed symptoms and rapid mood changes. Between-group comparisons provided preliminary vali-
Survival analyses using the standard definitions of syn- dation for the subtyping of bipolar disorder in youths. In
dromal recovery and recurrence (based on DSM-IV and general, in comparison with other subtypes, each bipolar
the literature) indicated that approximately 80% of youths subtype continued to show some category-specific symp-
with bipolar spectrum disorders achieved full recovery tomatology. For example, during follow-up, youths whose
about 2.5 years after onset of their index episode. How- initial diagnosis was bipolar I showed more syndromal,
ever, 1.5 years after full recovery, approximately 60% of the mixed/rapid cycling, and manic/hypomanic symptoms
participants had at least one syndromal recurrence. Com- than did those with bipolar disorder not otherwise speci-
pared to youths with bipolar disorder not otherwise spec- fied; youths with bipolar II spent more time in hypomania
ified, those with bipolar I and II were more likely to recover than did those with bipolar disorder not otherwise speci-
but also to have a less durable recovery. fied and more time in depression than did those with bi-
During the entire follow-up period, one-third of the par- polar I and bipolar disorder not otherwise specified; and
ticipants had at least one syndromal recurrence and 30% youths with bipolar disorder not otherwise specified spent
experienced more than two syndromal recurrences. Most significantly more time with subsyndromal symptoms
of these syndromal recurrences were major depressions, than did those with bipolar I and II. However, there was
followed by hypomanic, manic, and mixed episodes. In some symptom overlap among the different bipolar sub-
general, the polarity of the index episode predicted the po- types, especially bipolar I and II. Moreover, 25% of youths
larity of subsequent episodes. with bipolar II converted to bipolar I, and 38% of those
In addition to the analyses focusing only on recovery with bipolar disorder not otherwise specified converted to
and recurrence of syndromal symptoms, week-by-week bipolar I and II.
analyses provided a more in-depth clinical picture of the Although there were some differences in the demo-
course of bipolar disorder, showing that distinct periods of graphic and clinical factors associated with the outcome
full syndromal mood episodes exist in youths with bipolar variables measured (recovery, time symptomatic, and
spectrum disorders. However, these episodes are embed- changes in polarity), in general, early onset of bipolar dis-
ded in more prevailing and longer periods of subsyndro- order, presence of comorbid disorders, family history of
mal mood symptomatology. Youths with bipolar spectrum mood disorders (particularly mania/hypomania), low so-
disorders were symptomatic during 60% of the follow-up cioeconomic status, and non-Caucasian race were associ-
period, during which they spent about 2.5 times more ated with worse outcome. Long duration of illness was also
time with subsyndromal than with syndromal symptoma- associated with a lower likelihood of recovery, with each
tology. Mixed/cycling and depressive symptoms ac- year of illness decreasing the likelihood of recovery by 20%.
counted for the greatest proportion of time ill. In contrast, Before continuing the discussion of COBY’s findings, it
purely manic symptomatology, especially at the full syn- is important to note the limitations of this study. First, de-
dromal level, was less common. Rapid mood changes spite efforts to obtain precise information, the data col-
were ubiquitous, and psychotic symptoms were relatively lected through the Longitudinal Interval Follow-Up Evalu-
common, particularly in youths with bipolar I. Chronic ation is subject to retrospective recall bias. Although it
symptoms, defined as having any type of symptoms dur- appears that this instrument has adequate psychometric
ing 75% or more of the follow-up period, were present in properties (1, 4, 12), further studies using the methods de-
38% of the participants. Almost all of these chronic symp- scribed by Warshaw et al. (12) and including blind inter-
toms were subsyndromal and of the depressive type. viewers are warranted. Second, although COBY used the
The week-by-week analyses also shed light on the simi- standard definitions of course for recovery and recurrence
larities and differences in the longitudinal patterns of (1, 3, 18), the rates and duration of the mood episodes may
symptom phenomenology of youths with bipolar I and II change according to the duration criteria and symptom
and bipolar disorder not otherwise specified. Bipolar I was threshold severity chosen. Third, the results pertaining to
manifested by more time with subsyndromal than with youths with bipolar II should be considered tentative
syndromal symptoms. Most of the syndromal time was given the relatively small size of this group. However,
characterized by mixed/cycling or depressive symptoms, across all bipolar subtypes, after depression most syndro-
and most of the subsyndromal time was with subsyndro- mal recurrences were hypomanias. Finally, as most partic-
mal manic or mixed symptoms. Youths with bipolar II ipants were Caucasian and were recruited primarily from
spent equal amounts of time in syndromal and subsyndro- outpatient and, to a lesser extent, inpatient settings, the
mal states. The syndromal episodes were most commonly generalizability of the observations to other populations
Am J Psychiatry 166:7, July 2009 ajp.psychiatryonline.org 801

8. CHILDREN AND ADOLESCENTS WITH BIPOLAR SPECTRUM DISORDERS
remains uncertain. Nevertheless, nonreferred adolescents tent with adult data on high levels of morbidity associated
with bipolar disorder have been shown to have a similar with this subtype, youths with bipolar II had a greater
course and high morbidity (5). overall risk of recurrence and more depressive morbidity
Despite methodological differences, all existing studies compared to youths with bipolar I, and had rates of nonaf-
of the course of bipolar disorder in youths, regardless of fective comorbidity, suicidality, nonsuicidal self-injurious
country and source of ascertainment, show that the likeli- behaviors, functional impairment, and family history of
hood of recovery from the index episode is high (1–4). bipolar and other mood disorders comparable to those
However, as with adult populations, despite the high re- with bipolar I (6, 7, 32, 38–40). Also, bipolar II in youths ap-
covery rate, the rates of recurrence, persistence of subsyn- pears to be a far less stable phenotype than in adults; in
dromal clinical morbidity, and rapid and frequent changes this cohort, 25% of the bipolar II youths converted to bipo-
in mood polarity are also high, and most syndromal and lar I, a rate higher than that reported in adult studies (41).
subsyndromal recurrences are depressions (16, 19–23). It Since this disorder is mainly characterized by episodes of
does appear that the polarity of the index episode predicts syndromal and subsyndromal depression across the
the polarity of the subsequent episodes (21, 24–28), which lifespan, it is well appreciated that periods of hypomania
suggests the possibility of using specific psychosocial and can be misconstrued as normal fluctuations in mood or as
pharmacological treatments based on the polarity of the erratic behavior, and perhaps more so in adolescents (27,
index episode. 42), resulting in a high risk of misclassification as recurrent
The results of this and other emerging pediatric studies unipolar depression or other, nonaffective disorders.
suggest strong general similarities in the longitudinal Bipolar disorder not otherwise specified is character-
course of bipolar disorder in youths and adults, which is ized by rates of comorbidity, suicidality, functional impair-
mainly manifested by subsyndromal symptomatology ment (except hospitalizations), and family history of
and rapid mood changes (1–4, 29). However, there is evi- mood disorders equivalent to those in youths with bipolar
dence that very early onset confers greater liability for a I and II (6, 7, 32, 38–40). These findings, together with the
more chronic and fluctuating course, mixed/cycling epi- high rates of conversion to bipolar I or II, provide prelimi-
sodes, high rates of comorbid disorders, and increased nary validation of its nosological affinity with bipolar I and
rates of mood disorders in families (1, 3, 30–32). Converg- II disorder. It should be emphasized, however, that our
ing with these accounts are reports indicating that adults classification relied on the presence of an affective pheno-
whose onset of bipolar disorder dates to childhood have a type that differed from bipolar I or II due to failure to meet
more severe and chronic course, lower quality of life, and the DSM-IV duration requirements for these subtypes.
more episodes, changes in mood polarity, suicidality, and Thus, our findings are in accord with studies in the adult
comorbidity (33–35). literature (18, 42, 43) emphasizing the existence of clini-
Comparable with other findings in the literature (1–4, 6), cally relevant episodes of mania/hypomania that last for
we found that childhood-onset bipolar disorder, comorbid less time than required by DSM criteria. These episodes
disorders, positive family history for mood disorders, and are often overlooked because of the predominance of syn-
low socioeconomic status were associated with poorer out- dromal depression and subsyndromal manic/mixed
come. Moreover, the probability of recovery was inversely symptoms of short duration in its expression. Results from
related to duration of illness, which further underscores COBY suggest that bipolar disorder not otherwise speci-
the importance of early detection of illness and rapid im- fied is an episodic illness, albeit one that often comprises
plementation of stabilizing treatments. Such efforts may subsyndromal episodes that should be considered distinct
be of even greater urgency for youths with bipolar disorder from the symptomatology of youths with behavior disor-
who have risk factors associated with poorer outcome. ders and “severe mood dysregulation” (44).
Similar to findings in the literature on major depression In summary, although distinct episodes of full syndro-
(36), it appears that there are some differences in the fac- mal mood symptomatology as well as durable periods of
tors associated with the various indices of clinical out- euthymia can be identified in youths with bipolar disor-
come (recovery, recurrence, and amount of time symp- der, the course of bipolar spectrum disorders in children
tomatic). Moreover, as the polarity of the index episode and adolescents is predominantly characterized by sub-
was shown to convey different prognostic characteristics, syndromal and, much less frequently, syndromal epi-
it may be that these observations will be informative to sodes. Rapid mood changes are evident during these epi-
clinical practice. For example, since youths with depres- sodes, which are mainly of depressive and mixed polarity.
sion were seen to have more depressive recurrences, they During follow-up each bipolar subtype showed some dis-
may require more aggressive and specific therapies to re- tinct clinical characteristics and course, but there was
duce the risk of future depressive episodes. overlap in their symptoms and substantial conversion
To our knowledge, COBY is the first naturalistic, pro- from bipolar II and bipolar disorder not otherwise speci-
spective study of this affective subtype in youths—an im- fied into other bipolar subtypes. The course of bipolar dis-
portant avenue of research given the modal age of onset of order, the relative infrequency of syndromal DSM manic
bipolar II illness during adolescence (18, 27, 37). Consis- episodes, the effects of development in symptom manifes-
802 ajp.psychiatryonline.org Am J Psychiatry 166:7, July 2009

9. BIRMAHER, AXELSON, GOLDSTEIN, ET AL.
tation, and the high prevalence of comorbid disorders Version (K-SADS-PL): initial reliability and validity data. J Am
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nizing and managing this illness in youths. The recur-
Ryan N: A preliminary study of the Kiddie Schedule for Affec-
rence, chronicity, and psychosocial morbidity associated tive Disorders and Schizophrenia for School-Age Children Ma-
with this illness in critical developmental stages call for its nia Rating Scale for Children and Adolescents. J Child Adolesc
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Tabrizi MA, Davies M: The assessment of affective disorders in
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children and adolescents by semistructured interview: test-
retest reliability of the Schedule for Affective Disorders and
Received Oct. 23, 2008; revisions received Dec. 21, 2008, and Feb. 10, Schizophrenia for School-Age Children, Present Episode Ver-
2009; accepted Feb. 17, 2009 (doi: 10.1176/appi.ajp.2009.08101569). sion. Arch Gen Psychiatry 1985; 42:696–702
From the Department of Psychiatry, Western Psychiatric Institute and
11. Keller MB, Lavori PW, Friedman B, Nielsen E, Endicott J, Mc-
Clinic, University of Pittsburgh Medical Center, Pittsburgh; Department
Donald-Scott P, Andreasen NC: The Longitudinal Interval Fol-
of Psychiatry and Biobehavioral Sciences, David Geffen School of Med-
icine, University of California at Los Angeles; Department of Psychiatry low-up Evaluation: a comprehensive method for assessing out-
and Human Behavior, Warren Alpert Medical School, Brown University, come in prospective longitudinal studies. Arch Gen Psychiatry
Providence, R.I.; Department of Statistics, University of Pittsburgh. Ad- 1987; 44:540–548
dress correspondence and reprint requests to Dr. Birmaher, Western 12. Warshaw MG, Dyck I, Allsworth J, Stout RL, Keller MB: Maintain-
Psychiatric Institute and Clinic, 3811 O’Hara St., Pittsburgh, PA 15213; ing reliability in a long-term psychiatric study: an ongoing in-
birmaherb@upmc.edu (e-mail). ter-rater reliability monitoring program using the Longitudinal
Dr. Birmaher has participated in forums sponsored by Forest, Shire, Interval Follow-Up Evaluation. J Psychiatr Res 2001; 35:297–
Jazz Pharmaceuticals, Solvay, and Abcomm and receives royalties 305
from Random House and Lippincott Williams & Wilkins. Dr. Keller has
13. Weissman MM, Wickramaratne P, Adams P, Wolk S, Verdeli H,
received research support from, served as consultant to, or served on
speakers bureaus or advisory boards for Abbott, Bristol-Myers Olfson M: Brief screening for family psychiatric history: the
Squibb, CENEREX, Cephalon, Cypress Bioscience, Cyberonics, Forest, Family History Screen. Arch Gen Psychiatry 2000; 57:675–682
Janssen, JDS, Medtronic, Neuronetics, Novartis, Organon, Pfizer, 14. Petersen AC, Crockett L, Richards M, Boxer A: A self-report mea-
Roche, Solvay, and Wyeth. All other authors report no competing in- sure of pubertal status: reliability, validity, and initial norms. J
terests. Youth Adolesc 1988; 17:117–133
Supported by NIMH grants MH59929 (to Dr. Birmaher), MH59977 15. Hollingshead AB: Index of social status, in Research Instru-
(to Dr. Strober), and MH59691 (to Dr. Keller). ments in Social Gerontology, vol 2, Social Roles and Social Par-
The authors thank Carol Kostek for her assistance with manuscript ticipation. Edited by Mangen DJ, Peterson WA. Minneapolis,
preparation and Shelli Avenevoli, Ph.D., at NIMH, for her support and University of Minnesota Press, 1982
guidance.
16. Judd LL, Akiskal HS, Schettler PJ, Endicott J, Maser J, Solomon
DA, Leon AC, Rice JA, Keller MB: The long-term natural history
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