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  • 1. Article Four-Year Longitudinal Course of Children and Adolescents With Bipolar Spectrum Disorders: The Course and Outcome of Bipolar Youth (COBY) StudyBoris 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 predictedDavid 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 andMichael 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 byJeffrey 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 duringWonho 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 specifiedEunice 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, subsyndromalin 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 psychotherapyperiod 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 Bipolarmood 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 showedmixed symptoms. that during most of the follow-up time, youths experi- enced subsyndromal and syndromal mood symptoms This article is featured in this month’s AJP Audio.Am J Psychiatry 166:7, July 2009 ajp.psychiatryonline.org 795
  • 2. CHILDREN AND ADOLESCENTS WITH BIPOLAR SPECTRUM DISORDERSand frequent mood fluctuations (4). Twenty percent of the significantly later in youths with bipolar II than in youths with theyouths 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 maniaorder, and 25% of those with bipolar disorder not other- or hypomania being more common in youths with bipolar I thanwise 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 demographicdiatric bipolar disorder is not manifested only by discrete or clinical differences between those who continued in the studysyndromal recurrences but also by numerous subsyndro- and those who withdrew.mal episodes and mood changes, we conducted analysesof the week-by-week mood symptoms over the follow-up Proceduresperiod. 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 wereeries, 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 thespecific 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). Thesemonths with DSM-IV bipolar I or II disorder or operationally de- scales use numeric values that have been operationally linked tofined bipolar disorder not otherwise specified. Youths with COBY- the DSM-IV criteria; DSM-IV criteria information is gathered indefined bipolar disorder not otherwise specified were previously the interview and then translated into ratings for each week of theshown 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 Ratingpared 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 fullmood 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 theother physicians (4.8%). They were enrolled independent of cur- Family History Screen (13). The Petersen Pubertal Developmentrent 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 toassessment. Participants had been prospectively interviewed ev- child psychiatrists or psychologists, who confirmed the diagnosesery 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 correlationspecified: 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 (usingspecified 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 concordanceorder 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 ofdisorder not otherwise specified. There were no between-group the K-SADS-P were used as an additional assessment of mooddifferences in Tanner stages II or III. The mean age at onset of symptom severity for the week when symptoms were most severemood 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 Statusof age at onset). The onset of mood symptoms and episodes was Rating Scales for the 4 weeks prior to each follow-up assessment796 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 SpecifiedCharacteristic (N=413) (N=244) (N=28) (N=141) Statistic df p Mean SD Mean SD Mean SD Mean SDAge 12.6 3.3 12.8a 3.2 14.8b 2.7 11.9c 3.2 F=11.0 2, 140 <0.001Hollingshead 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 0.07Caucasian 339 82.1 200 82.0 24 85.7 115 81.6 χ2=0.3 2 0.9Living with both natural parents 174 42.1 94 38.5 17 60.7 6 44.7 χ2=5.6 2 0.06Tanner 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 SDAge 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=19.5Duration 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=4.5Duration 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 84.4bPsychosis 92 22.3 69 28.3a 4 14.3a,b 19 13.5b χ2=12.4 2 0.002Any comorbidity 351 85.0 206 84.4 22 78.6 123 87.2 Fisher’s exact 0.4 testFamily 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 pressiona 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. Similartion of the K-SADS-P for the same period showed Spearman cor- to previous studies (16), “change in mood polarity” was defined asrelations 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 weeksDefinitions 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 ofof 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 usedified. 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 AnalysesDSM-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 duringthe entire follow-up period was computed for each participant, portional hazards regressions (17). The numerous ongoing moodbased 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-groupno mood symptoms) (4, 16). Time to recovery from the index epi- analyses of the week-by-week syndromal and subsyndromalsode was measured from the onset of the index episode. Partici- symptoms, stratifying by bipolar subtype. Differences within andpants were considered to have a recurrence (new episode) if they between groups were analyzed using standard parametric andhad 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 DISORDERSTABLE 2. Summary of Recovery and Recurrence in 413 Youths With Bipolar Spectrum Disorders, by Bipolar Subtype a Bipolar Disorder Analyses Not OtherwiseVariable 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 0.09Rate 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 MedianTime to recovery from the 123.7 78.3a 76.9a 180.0b 14.12 2 0.001 index episode (weeks)cTime to recurrence (weeks)d 71.0 69.0a 45.0a 82.0b 7.73 2 0.02a 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 andbipolar 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 andbipolar disorder, presence of any comorbid disorder, and family having higher socioeconomic status was associated with ahistory of mood disorders, as well as interactions between thesevariables, 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 interactionsinterest 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 fvided 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 theircents with onset of their episodes at or after age 12. Analyses in- index episode (Table 2). Higher rates of, and shortercluding 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 disorderated (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 wereRecovery from the index episode. Overall, 81.4% of major depressive episodes (59.5%), followed by hypomanicthe 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 otherwisecompared to those with bipolar disorder not otherwise specified, 64% (109/171) of the first recurrences were majorspecified, 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 whoseotherwise specified (Figure 1). In addition to the standard index episode was mania, the majority of first recurrences8-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 associatedsus bipolar I and II, hazard ratio=0.62, 95% CI=0.49–0.97); with bipolar I and bipolar II (versus bipolar disorder notchildren with childhood onset (versus adolescents with otherwise specified, hazard ratio=1.37, 95% CI=1.01–1.88);798 ajp.psychiatryonline.org Am J Psychiatry 166:7, July 2009
  • 5. BIRMAHER, AXELSON, GOLDSTEIN, ET AL.FIGURE 1. Survival Analysis of Recovery From Index Epi- FIGURE 2. Survival Analysis of Recurrence After Recoverysode 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 Weeksa 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 morefirst- or second-degree relatives (hazard ratio=1.38, 95% follow-up time asymptomatic than did those with bipolarCI=1.04–1.84). No other significant predictors or interac- disorder not otherwise specified. Youths with bipolar I andtions were found. II spent similar amounts of time with syndromal symp- toms but more time than those with bipolar disorder notWeek-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 timespent approximately 40% of the time during the follow-up with subsyndromal symptoms than did those with theperiod 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 otherwisesyndromal depression or mixed/cycling than in syndro- specified, youths with bipolar II spent more time in majormal 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 timeWithin-group analyses. Analyses within each bipolar with mixed/cycling symptoms than did those with bipolarsubtype showed that youths with bipolar I and bipolar dis- disorder not otherwise specified. By definition, youthsorder 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 orsymptoms. 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 subsyndromaldromal and subsyndromal symptoms. While experiencing manic symptoms compared to those with bipolar II. Forsyndromal 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 anywith 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), adolescentssubsyndromal mixed symptoms than with the other two with childhood onset (versus adolescents with adolescentsubsyndromal 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 ortime spent in each subsyndromal polarity. For all compar- interactions were found. Except for bipolar I and II predict-Am J Psychiatry 166:7, July 2009 ajp.psychiatryonline.org 799
  • 6. CHILDREN AND ADOLESCENTS WITH BIPOLAR SPECTRUM DISORDERSTABLE 3. Weekly Symptomatic Status and Changes in Mood Polarity in 413 Youths With Bipolar Spectrum Disorders, byBipolar Subtypea Bipolar Disorder Analyses Total Sample Bipolar I Disorder Bipolar II Disorder Not OtherwiseSymptomatology (N=413) (N=244) (N=28) Specified (N=141) χ2 df p Mean SD Mean SD Mean SD Mean SDPercentage 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 0.1a 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 yearnon-Caucasian predicting more time with subsyndromal in 51.1%, 10 times or more per year in 38.7%, and moresymptomatology, 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 toPatients 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 nocalculated 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 withmately 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 greaterdromal criteria for mood episodes. Most of these chronic number of changes in mood polarity per year. There weresymptoms 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 anddefined as having a score of 3 (definitely present) for delu- From Bipolar Disorder Not Otherwise Specifiedsions and/or hallucinations on the Psychiatric Status Rating to Bipolar I or IIScales. Overall, 16% of the participants experienced psy- Of the 169 youths with bipolar II and bipolar disorderchotic 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 specifiedthose with bipolar disorder not otherwise specified. converted to bipolar I, and 18.4% (26/141) with bipolarChange in mood polarity. Shifts in mood polarity oc- disorder not otherwise specified converted to bipolar IIcurred 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).800 ajp.psychiatryonline.org Am J Psychiatry 166:7, July 2009
  • 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 ofand 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. Indromal recovery and recurrence (based on DSM-IV and general, in comparison with other subtypes, each bipolarthe 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 whoseabout 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 symptomsparticipants 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 hypomaniaified, 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; andticipants had at least one syndromal recurrence and 30% youths with bipolar disorder not otherwise specified spentexperienced more than two syndromal recurrences. Most significantly more time with subsyndromal symptomsof these syndromal recurrences were major depressions, than did those with bipolar I and II. However, there wasfollowed 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 youthslarity 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 toand 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 outcomefull syndromal mood episodes exist in youths with bipolar variables measured (recovery, time symptomatic, andspectrum 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 ofmal 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 alsotime with subsyndromal than with syndromal symptoma- associated with a lower likelihood of recovery, with eachtology. 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, itpurely 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 itsymptoms, defined as having any type of symptoms dur- appears that this instrument has adequate psychometricing 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 recurrencelarities and differences in the longitudinal patterns of (1, 3, 18), the rates and duration of the mood episodes maysymptom phenomenology of youths with bipolar I and II change according to the duration criteria and symptomand bipolar disorder not otherwise specified. Bipolar I was threshold severity chosen. Third, the results pertaining tomanifested by more time with subsyndromal than with youths with bipolar II should be considered tentativesyndromal 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 fromspent equal amounts of time in syndromal and subsyndro- outpatient and, to a lesser extent, inpatient settings, themal states. The syndromal episodes were most commonly generalizability of the observations to other populationsAm J Psychiatry 166:7, July 2009 ajp.psychiatryonline.org 801
  • 8. CHILDREN AND ADOLESCENTS WITH BIPOLAR SPECTRUM DISORDERSremains uncertain. Nevertheless, nonreferred adolescents tent with adult data on high levels of morbidity associatedwith bipolar disorder have been shown to have a similar with this subtype, youths with bipolar II had a greatercourse 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-injuriouscountry and source of ascertainment, show that the likeli- behaviors, functional impairment, and family history ofhood of recovery from the index episode is high (1–4). bipolar and other mood disorders comparable to thoseHowever, 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; indromal 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 ofdoes appear that the polarity of the index episode predicts syndromal and subsyndromal depression across thethe polarity of the subsequent episodes (21, 24–28), which lifespan, it is well appreciated that periods of hypomaniasuggests the possibility of using specific psychosocial and can be misconstrued as normal fluctuations in mood or aspharmacological 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 ofand rapid mood changes (1–4, 29). However, there is evi- mood disorders equivalent to those in youths with bipolardence that very early onset confers greater liability for a I and II (6, 7, 32, 38–40). These findings, together with themore 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 andrates of mood disorders in families (1, 3, 30–32). Converg- II disorder. It should be emphasized, however, that ouring 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 meetmore 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 adultcomorbidity (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 forwe found that childhood-onset bipolar disorder, comorbid less time than required by DSM criteria. These episodesdisorders, 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/mixedcome. Moreover, the probability of recovery was inversely symptoms of short duration in its expression. Results fromrelated 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 comprisesplementation of stabilizing treatments. Such efforts may subsyndromal episodes that should be considered distinctbe 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 oftors 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 childrentomatic). 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 wasduce 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 manicbipolar 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 Ammay account, at least in part, for the difficulties in recog- Acad Child Adolesc Psychiatry 1997; 36:980–988 9. Axelson D, Birmaher BJ, Brent D, Wassick S, Hoover C, Bridge J,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 Adolescprompt recognition and the development of more effica- Psychopharmacol 2003; 13:463–470cious treatments, particularly since each year of illness ap- 10. Chambers WJ, Puig-Antich J, Hirsch M, Paez P, Ambrosini PJ, Tabrizi MA, Davies M: The assessment of affective disorders inpears to decrease the likelihood of recovery. 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; 42:696–702From 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 PsychiatryProvidence, R.I.; Department of Statistics, University of Pittsburgh. Ad- 1987; 44:540–548dress 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 305from 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 onspeakers bureaus or advisory boards for Abbott, Bristol-Myers Olfson M: Brief screening for family psychiatric history: theSquibb, CENEREX, Cephalon, Cypress Bioscience, Cyberonics, Forest, Family History Screen. 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