Birmaher et al 2009; coby study

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Birmaher et al 2009; coby study

  1. 1. Am J Psychiatry 166:7, July 2009 795 Article ajp.psychiatryonline.org This article is featured in this month’s AJP Audio. Four-Year Longitudinal Course of Children and Adolescents With Bipolar Spectrum Disorders: The Course and Outcome of Bipolar Youth (COBY) Study Boris Birmaher, M.D. David Axelson, M.D. Benjamin Goldstein, M.D. Michael Strober, Ph.D. Mary Kay Gill, M.S.N. Jeffrey Hunt, M.D. Patricia Houck, M.S.H. Wonho Ha, Ph.D. Satish Iyengar, Ph.D. Eunice Kim, Ph.D. Shirley Yen, Ph.D. Heather Hower, M.S.W. Christianne Esposito-Smythers, Ph.D. Tina Goldstein, Ph.D. Neal Ryan, M.D. Martin Keller, M.D. Objective: The authors sought to assess the longitudinal course of youths with bi- polar spectrum disorders over a 4-year period. Method: At total of 413 youths (ages 7– 17 years) with bipolar I disorder (N=244), bipolar II disorder (N=28), and bipolar dis- order not otherwise specified (N=141) were enrolled in the study. Symptoms were ascertained retrospectively on aver- age every 9.4 months for 4 years using the Longitudinal Interval Follow-Up Evalua- tion. Rates and time to recovery and re- currence and week-by-week symptomatic status were analyzed. Results: Approximately 2.5 years after onset of their index episode, 81.5% of the participants had fully recovered, but 1.5 years later 62.5% had a syndromal recur- rence, particularly depression. One-third of the participants had one syndromal re- currence, and 30% had two or more. The polarity of the index episode predicted that of subsequent episodes. Participants were symptomatic during 60% of the fol- low-up period, particularly with subsyn- dromal symptoms of depression and mixed polarity, with numerous changes in mood polarity. Manic symptomatology, especially syndromal, was less frequent, and bipolar II was mainly manifested by depressive symptoms. Overall, 40% of the participants had syndromal or subsyndro- mal symptoms during 75% of the follow- up period, and 16% of the participants ex- perienced psychotic symptoms during 17% the follow-up period. Twenty-five percent of youths with bipolar II con- verted to bipolar I, and 38% of those with bipolar disorder not otherwise specified converted to bipolar I or II. Early onset, di- agnosis of bipolar disorder not otherwise specified, long illness duration, low socio- economic status, and family history of mood disorders were associated with poorer outcomes. Conclusions: Bipolar spectrum disorders in youths are characterized by episodic ill- ness with subsyndromal and, less fre- quently, syndromal episodes with mainly depressive and mixed symptoms and rapid mood changes. (Am J Psychiatry 2009; 166:795–804) Prospective naturalistic studies of children and adoles- cents with bipolar disorder (mainly subtype I) have shown that while rates of recovery from index episodes are high, in the range of 70%–100%, of those who recover, up to 80% will experience one or more syndromal recurrences over a period of 2 to 5 years (1–4). Moreover, prospective studies have shown that, similar to findings reported for adults (1, 3, 4), youths with bipolar disorder experience frequent mood fluctuations of varying intensities throughout 60%– 80% of the follow-up time, particularly depressive and mixed symptoms. Factors associated with worse longitudinal outcome in- clude early age at illness onset, long illness duration, mixed episodes, rapid cycling, psychosis, subsyndromal symptoms, comorbid disorders, low socioeconomic sta- tus, exposure to negative life events, lack of psychotherapy treatment, poor adherence to pharmacological treatment, and family psychopathology (1–6). A prior study from the Course and Outcome of Bipolar Youth (COBY) program that followed 263 youths with bi- polar spectrum disorders for an average of 2 years showed that during most of the follow-up time, youths experi- enced subsyndromal and syndromal mood symptoms
  2. 2. 796 Am J Psychiatry 166:7, July 2009 CHILDREN AND ADOLESCENTS WITH BIPOLAR SPECTRUM DISORDERS ajp.psychiatryonline.org and frequent mood fluctuations (4). Twenty percent of the youths with bipolar II disorder converted to bipolar I dis- order, and 25% of those with bipolar disorder not other- wise specified converted to bipolar I or II disorder. The aim of the present study was to extend COBY’s prior find- ings in a larger sample of youths with bipolar spectrum disorders followed for a longer time. For this purpose, the data were evaluated with two complementary sets of anal- yses. In the first, to compare our results with those of the existing literature, we conducted analyses using survival analytic techniques and the standard definitions of syn- dromal recovery and recurrence. In the second, since pe- diatric bipolar disorder is not manifested only by discrete syndromal recurrences but also by numerous subsyndro- mal episodes and mood changes, we conducted analyses of the week-by-week mood symptoms over the follow-up period. Subsequent reports will investigate how outcomes are affected by other factors, such as subsyndromal recov- eries, suicidal behaviors, health services utilization, psy- chosocial functioning, exposure to negative life events, specific comorbid disorders, and treatment. Method Participants The methods for COBY have been described in detail elsewhere (4, 7). Briefly, the study included youths ages 7 to 17 years 11 months with DSM-IV bipolar I or II disorder or operationally de- fined bipolar disorder not otherwise specified. Youths with COBY- defined bipolar disorder not otherwise specified were previously shown to convert to bipolar I or II and to have a comparable but less severe clinical picture, a similar family history, similar rates of comorbid disorders, and a similar longitudinal outcome com- pared with youths with bipolar I (4, 7). Youths with schizophrenia, mental retardation, autism, and mood disorders secondary to substances, medications, or medi- cal conditions were excluded from the study. Participants were recruited from outpatient clinics (67.6%), in- patient units (14.3%), advertisements (13.3%), and referrals from other physicians (4.8%). They were enrolled independent of cur- rent mood state or treatment status. The analyses in this study are based on the prospective evalua- tion of 413 youths, including 244 (59.1%) with bipolar I disorder, 28 (6.8%) with bipolar II disorder, and 141 (34.1%) with bipolar disorder not otherwise specified who had at least one follow-up assessment. Participants had been prospectively interviewed ev- ery 37.5 weeks (SD=20.8) for an average of 191.5 weeks (SD=75.7). Youths with bipolar II were followed significantly longer (227.4 weeks [SD=76.6]) than those with the other two bipolar subtypes (bipolar I: 183.2 weeks [SD=71.8]; bipolar disorder not otherwise specified: 198.7 weeks [SD=79.8]; F=5.4, p=0.005). At intake, participants with bipolar disorder not otherwise specified were the youngest, followed by those with bipolar I and then those with bipolar II (Table 1). More youths with bipolar dis- order not otherwise specified were in Tanner stage I of sexual de- velopment than those with bipolar II, and more youths with bi- polar II were in Tanner stages IV or V than those with bipolar disorder not otherwise specified. There were no between-group differences in Tanner stages II or III. The mean age at onset of mood symptoms was 8.4 years, and the mean age at onset of DSM-IV mood episodes was 9.3 years (see below for the definition of age at onset). The onset of mood symptoms and episodes was significantly later in youths with bipolar II than in youths with the other two bipolar subtypes. As expected, by definition, the polar- ity of the index episode reflected the bipolar subtype, with mania or hypomania being more common in youths with bipolar I than in those with bipolar II or bipolar disorder not otherwise speci- fied. However, youths with bipolar II had significantly more de- pressive index episodes than youths with the other two subtypes. Youths with bipolar I had more lifetime psychosis than those with bipolar disorder not otherwise specified (for all above compari- sons, p values were <0.05 and Cohen’s d ranged from 0.3 to 0.9). There were no other significant between-group differences. The retention rate was 86%, with 93% of participants complet- ing at least one follow-up interview. Except for lower rates of anx- iety disorders in youths who dropped out of the study (54.5% compared with 38.7%; p=0.02), there were no other demographic or clinical differences between those who continued in the study and those who withdrew. Procedures Each participating university’s institutional review board ap- proved the study, and consent was obtained from the participat- ing youths and their parents. At intake, youths and parents were directly interviewed for the presence of current and lifetime psy- chiatric disorders in the youths. The instruments used were the Schedule for Affective Disorders and Schizophrenia for School- Age Children—Present and Lifetime Version (K-SADS-PL) (8), the Kiddie Mania Rating Scale (K-MRS) (9), and the depression sec- tion of the K-SADS-PL (10). Longitudinal changes in psychiatric symptoms since the previ- ous evaluation were assessed using the Longitudinal Interval Fol- low-Up Evaluation (11) and tracked on a week-by-week basis us- ing this instrument’s Psychiatric Status Rating Scales (12). These scales use numeric values that have been operationally linked to the DSM-IV criteria; DSM-IV criteria information is gathered in the interview and then translated into ratings for each week of the follow-up period. The ratings indicate the severity level of an epi- sode as well as whether the patient has recovered or had a recur- rence. For mood disorders, scores on the Psychiatric Status Rating Scales range from 1 for no symptoms to 2–4 for varying levels of subthreshold symptoms and impairment to 5–6 for meeting full criteria with different degrees of severity or impairment. The con- sensus scores obtained after interviewing parents and their chil- dren were used for the analyses. Family history of mood disorders was ascertained using the Family History Screen (13). The Petersen Pubertal Development Scale (14) and the equivalent Tanner stages were used to evaluate and categorize pubertal stages. Socioeconomic status was ascer- tained using the four-factor Hollingshead scale (15). All assessments were conducted by research staff trained to reli- ably administer the interviews; interview results were presented to child psychiatrists or psychologists, who confirmed the diagnoses and the Psychiatric Status Rating Scales scores. The overall K- SADS-PL kappa coefficients for psychiatric disorders were ≥0.8. The intraclass correlation coefficients for the K-MRS and the K- SADS-P depression section were ≥0.95. The intraclass correlation coefficients for syndromal and subsyndromal mood disorders as- certained through the Psychiatric Status Rating Scales (using methods described elsewhere [12]) were ≥0.75; the intraclass coef- ficient correlations and the Kendall’s coefficients of concordance were between 0.74 and 0.79 for a major depressive episode and be- tween 0.60 and 0.67 for mania/hypomania. During the follow-up, the K-MRS and the depression section of the K-SADS-P were used as an additional assessment of mood symptom severity for the week when symptoms were most severe during the month prior to interview. A comparison of the maxi- mum scores for depression and mania on the Psychiatric Status Rating Scales for the 4 weeks prior to each follow-up assessment
  3. 3. Am J Psychiatry 166:7, July 2009 797 BIRMAHER, AXELSON, GOLDSTEIN, ET AL. ajp.psychiatryonline.org and the maximum scores on the K-MRS and the depression sec- tion of the K-SADS-P for the same period showed Spearman cor- relations of 0.82 (p<0.0001) and 0.77 (p<0.0001), respectively. Definitions of Clinical Course Age at onset of bipolar disorder was defined as the age at onset of a DSM-IV mood episode or an episode fulfilling the COBY’s modified DSM-IV criteria for bipolar disorder not otherwise spec- ified. The minimum age at onset was arbitrarily set at age 4. The duration of bipolar disorder was calculated from the age at onset. The index episode was defined as the current or most recent DSM-IV mood episode. The percentage of follow-up weeks spent asymptomatic or symptomatic in the different mood symptom categories during the entire follow-up period was computed for each participant, based on Psychiatric Status Rating Scales scores. Full recovery was defined as 8 consecutive weeks with a score ≤2 (minimal or no mood symptoms) (4, 16). Time to recovery from the index epi- sode was measured from the onset of the index episode. Partici- pants were considered to have a recurrence (new episode) if they had a Psychiatric Status Rating Scales score ≥5 with a duration of 1 week for mania/hypomania or 2 weeks for depression. Similar to previous studies (16), “change in mood polarity” was defined as a switch between depression (rating ≥3) and mania/hypomania (rating ≥3) or vice versa with or without any intervening weeks with no symptoms or when ratings for 1 week included both ma- nia/hypomania and depression scores ≥3. This definition of change in mood polarity is not the equivalent of DSM rapid cy- cling. For rapid cycling as well as for mixed episodes, COBY used the DSM-IV definitions. Statistical Analyses The syndromal recoveries and recurrences manifested in bipo- lar disorder were evaluated using survival analyses and Cox pro- portional hazards regressions (17). The numerous ongoing mood changes and periods of subsyndromal symptoms of bipolar dis- order were evaluated using within-group and between-group analyses of the week-by-week syndromal and subsyndromal symptoms, stratifying by bipolar subtype. Differences within and between groups were analyzed using standard parametric and nonparametric univariate tests. TABLE 1. Demographic and Clinical Characteristics of 413 Youths With Bipolar Spectrum Disorders, by Bipolar Subtypea Characteristic Total Sample (N=413) Bipolar I Disorder (N=244) Bipolar II Disorder (N=28) Bipolar Disor- der Not Other- wise Specified (N=141) Analyses Statistic df p Mean SD Mean SD Mean SD Mean SD Age 12.6 3.3 12.8a 3.2 14.8b 2.7 11.9c 3.2 F=11.0 2, 140 <0.001 Hollingshead Index of Social Status 3.4 1.2 3.4 1.3 3.8 0.9 3.4 1.1 Kruskal-Wallis test=3.1 2 0.2 N % N % N % N % Male 221 53.5 123 50.4 12 42.9 86 61.0 χ2=5.4 2 0.07 Caucasian 339 82.1 200 82.0 24 85.7 115 81.6 χ2=0.3 2 0.9 Living with both natural parents 174 42.1 94 38.5 17 60.7 6 44.7 χ2=5.6 2 0.06 Tanner stage of sexual development χ2=9.6 4 0.05 I 87 27.0 47 25.5a 2 7.4b 38 34.2a II–III 89 27.6 50 27.2 8 29.6 31 27.9 IV–V 146 45.3 87 47.3a, b 17 63.0a 42 37.8b Mean SD Mean SD Mean SD Mean SD Age at onset of mood symptoms (years) 8.4 4.0 8.4a 4.3 10.5b 3.9 7.9a 3.4 Kruskal-Wallis test=19.5 2 0.009 Duration of mood symptoms (years) 4.4 3.0 4.5 3.1 4.3 2.6 4.2 2.9 F=0.4 2, 410 0.7 Age at onset of a DSM mood episode (years)b 9.3 3.9 9.3a 4.1a 11.8b 3.2 8.7a 3.5 Kruskal-Wallis test=4.5 2 0.001 Duration of bipolar disorder (years)c 3.3 2.5 3.5 2.7 3.0 1.3 3.2 2.3 Kruskal-Wallis test=0.5 2 0.8 N % N % N % N % Polarity of index episode χ2=229.29 0.001 Depressed 58 14.0 34 7.0a 11 39.3b 13 9.2a Hypomanic 34 8.2 17 13.9a 10 35.7b 7 5.0a Manic 77 18.6 77 31.6a 0 0.0b 0 0.0b Mixed 70 17.0 68 27.9a 0 0.0b 2 1.4b Not otherwise specified 174 42.1 48 19.7a 7 25.0a 119 84.4b Psychosis 92 22.3 69 28.3a 4 14.3a,b 19 13.5b χ2=12.4 2 0.002 Any comorbidity 351 85.0 206 84.4 22 78.6 123 87.2 Fisher’s exact test 0.4 Family history First-degree relative with mania or hypomania 143 36.8 87 38.0 12 44.4 44 33.1 χ2=1.6 2 0.4 First-degree relative with depres- sion 295 75.6 168 73.0 23 85.2 104 78.2 χ2=2.6 2 0.3 Second-degree relative with ma- nia or hypomania 143 37.6 80 36.0 14 50.0 49 37.7 χ2=2.1 2 0.4 Second-degree relative with de- pression 276 72.3 157 70.4 25 89.3 94 71.8 χ2=4.4 2 0.1 a Different subscripts indicate significant pairwise differences at p≤0.05. b Age 4 is set as the minimum value. c Calculated from age at onset of any DSM mood episode.
  4. 4. 798 Am J Psychiatry 166:7, July 2009 CHILDREN AND ADOLESCENTS WITH BIPOLAR SPECTRUM DISORDERS ajp.psychiatryonline.org About 14% of the sample had their most recent mood episode offset and recovered before intake. Since the analyses with and without these participants yielded similar results, all participants were included in the analyses. The data were censored after participants with bipolar II and bipolar disorder not otherwise specified converted to other bipo- lar subtypes. For all of these analyses, the effects of demographic variables, age, bipolar subtype, psychosis, age at bipolar onset, duration of bipolar disorder, presence of any comorbid disorder, and family history of mood disorders, as well as interactions between these variables, were evaluated. Variables were examined univariately, and those that were significantly associated with the outcome of interest were analyzed using multiple linear regressions. Analyz- ing the data using generalized linear models yielded similar re- sults. To assess the effects of age on outcome, the sample was di- vided into three groups: children <12 years old, adolescents ≥12 years old with onset of their episodes prior to age 12, and adoles- cents with onset of their episodes at or after age 12. Analyses in- cluding age or pubertal status yielded similar results. Thus, only the results including age are presented. Also, since bipolar sub- type and polarity of the index bipolar episode were highly associ- ated (φ=0.75, p≤0.0001) (also see Table 1), only the bipolar sub- type was included in the analyses. All p values are based on two-tailed tests with α set at 0.05. Results Survival Analyses Recovery from the index episode. Overall, 81.4% of the participants had full recovery, a median of 123.7 weeks after the onset of the index episode (Table 2). Youths with bipolar I showed significantly higher rates of recovery compared to those with bipolar disorder not otherwise specified, and those with bipolar I and II had shorter times to recovery compared to those with bipolar disorder not otherwise specified (Figure 1). In addition to the standard 8-week duration criterion for recovery, in analyses using 2, 4, and 6 weeks with minimal or no mood symptoms, rates of recovery were 88%, 84%, and 81%, respectively. A lower likelihood of full recovery was associated with a diagnosis of bipolar disorder not otherwise specified (ver- sus bipolar I and II, hazard ratio=0.62, 95% CI=0.49–0.97); children with childhood onset (versus adolescents with adolescent onset, hazard ratio=0.50, 95% CI=0.37–0.67; versus adolescents with childhood onset, hazard ratio= 0.70, 95% CI=0.50–0.99); non-Caucasian race (hazard ra- tio=0.60, 95% CI=0.42–0.84); longer duration of illness (hazard ratio=0.83, 95% CI=0.78–0.88); and a family his- tory of mania/hypomania in first- or second-degree rela- tives (hazard ratio=0.79, 95% CI=0.63–0.99). Conversely, the interaction of living with both biological parents and having higher socioeconomic status was associated with a greater likelihood of recovery (hazard ratio=1.23, 95% CI= 1.01–1.51). No other significant predictors or interactions were found. Recurrence after recovery from index episode. Of the youths who recovered, 62.5% had a syndromal recur- rence a median of 71 weeks after recovering from their index episode (Table 2). Higher rates of, and shorter times to, recurrence occurred among youths with bipo- lar I and II as compared to those with bipolar disorder not otherwise specified (Figure 2). Participants who recovered had a mean of 1.1 syndromal recurrences (SD=1.2) during the 4-year follow-up; 33% (110/336) had one recurrence, 20% (66/336) had two recur- rences, and 10% (34/336) had three or more recurrences during the follow-up period. Across all bipolar subtypes, most syndromal recurrences after the index episode were major depressive episodes (59.5%), followed by hypomanic (20.9%), manic (14.8%), and mixed (4.8%) episodes. Inter- estingly, for youths whose index episode was a major de- pression, a mixed episode, hypomania, or not otherwise specified, 64% (109/171) of the first recurrences were major depressions, followed by mania/hypomania (30%; 52/171) and then mixed episodes (6%; 10/171). For youths whose index episode was mania, the majority of first recurrences were mania/hypomania (59%; 23/39), followed by depres- sion (41%; 16/39). A subanalysis including only partici- pants with bipolar I in an age band similar to that of a prior bipolar I longitudinal study (3) yielded similar results. An increased likelihood of recurrence was associated with bipolar I and bipolar II (versus bipolar disorder not otherwise specified, hazard ratio=1.37, 95% CI=1.01–1.88); TABLE 2. Summary of Recovery and Recurrence in 413 Youths With Bipolar Spectrum Disorders, by Bipolar Subtypea Total Sample Bipolar I Disorder Bipolar II Disorder Bipolar Disorder Not Otherwise Specified Analyses Variable χ2 df p N % N % N % N % Rate of recovery 336/413 81.4 207/244a 84.8 21/28a,b 75.0 108/141b 76.6 4.80 2 0.09 Rate of recurrenceb 210/336 62.5 135/207a 65.2 17/21a 81.0 58/108b 53.7 7.27 2 0.03 Median Median Median Median Time to recovery from the index episode (weeks)c 123.7 78.3a 76.9a 180.0b 14.12 2 0.001 Time to recurrence (weeks)d 71.0 69.0a 45.0a 82.0b 7.73 2 0.02 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.
  5. 5. Am J Psychiatry 166:7, July 2009 799 BIRMAHER, AXELSON, GOLDSTEIN, ET AL. ajp.psychiatryonline.org lower socioeconomic status (hazard ratio=0.87, 95% CI= 0.77–0.97); and a family history of mania/hypomania in first- or second-degree relatives (hazard ratio=1.38, 95% CI=1.04–1.84). No other significant predictors or interac- tions were found. Week-by-Week Mood Analyses Analyses for the entire sample. Overall, participants spent approximately 40% of the time during the follow-up period asymptomatic and 60% symptomatic (41.8% sub- syndromal and 16.6% with syndromal symptomatology) (Table 3). Participants spent significantly more time in syndromal depression or mixed/cycling than in syndro- mal mania/hypomania. There were no significant differ- ences in time spent in each subsyndromal polarity. Within-group analyses. Analyses within each bipolar subtype showed that youths with bipolar I and bipolar dis- order not otherwise specified spent significantly more fol- low-up time with subsyndromal than with syndromal symptoms. For youths with bipolar II, there was no differ- ence in the proportion of follow-up time spent with syn- dromal and subsyndromal symptoms. While experiencing syndromal symptoms, all three bipolar subtypes spent more time with depression and mixed/cycling symptoms than with mania/hypomania. While experiencing subsyn- dromal symptoms, youths with bipolar I spent more time with subsyndromal mania and mixed symptoms than with subsyndromal depression, and youths with bipolar disorder not otherwise specified spent more time with subsyndromal mixed symptoms than with the other two subsyndromal polarities. For youths with bipolar II, there were no significant differences in the amount of follow-up time spent in each subsyndromal polarity. For all compar- isons, p values were ≤0.05 and values for Cohen’s ds ranged from 0.45 to 1.3. Between-group analyses. Comparisons between bipo- lar subtypes showed that youths with bipolar I spent more follow-up time asymptomatic than did those with bipolar disorder not otherwise specified. Youths with bipolar I and II spent similar amounts of time with syndromal symp- toms but more time than those with bipolar disorder not otherwise specified. In contrast, youths with bipolar disor- der not otherwise specified spent significantly more time with subsyndromal symptoms than did those with the other two bipolar subtypes. Within syndromal periods, youths with bipolar I and II spent more time with hypo- mania than did those with bipolar disorder not otherwise specified, youths with bipolar II spent more time in major depression episodes than did those with the other two bi- polar subtypes, and youths with bipolar I spent more time with mixed/cycling symptoms than did those with bipolar disorder not otherwise specified. By definition, youths with bipolar II and bipolar disorder not otherwise speci- fied did not spend any weeks with syndromal mania or mixed symptoms. Within subsyndromal periods, partici- pants with bipolar I spent more weeks with subsyndromal manic symptoms compared to those with bipolar II. For all comparisons, p values were ≤0.05 and values for Co- hen’s ds ranged from 0.24 to 0.63. Multiple linear regression models. The following vari- ables were associated with more follow-up weeks with any mood symptoms: low socioeconomic status (t=4.28, p<0.001), children with childhood onset (versus adoles- cents with adolescent onset, t=5.07, p<0.001), adolescents with childhood onset (versus adolescents with adolescent onset, t=4.05, p<0.001), and presence of any comorbid dis- order (t=2.62, p=0.009). No other significant predictors or interactions were found. Except for bipolar I and II predict- FIGURE 1. Survival Analysis of Recovery From Index Epi- sode in Youths With Bipolar Disorder, by Bipolar Subtypea a Log-rank χ2=14.01, p=0.0001. The index episode was defined as the current or most recent syndromal DSM episode at intake. To as- certain real duration of illness, time to recovery was calculated from the onset of the index episode; therefore, for some youths, the duration of the index episode exceeds the length of the pro- spective follow-up period. 0.6 0.4 0.2 0.0 1.0 0.8 CumulativeProportionRecovered 4002000 600 Time to Recovery in Weeks Bipolar I disorder (N=244) Bipolar II disorder (N=28) Bipolar disorder not otherwise specified (N=141) FIGURE 2. Survival Analysis of Recurrence After Recovery From Index Episode of Bipolar Disorder, by Bipolar Subtypea a Log-rank χ2=7.7, p=0.02. Time to recurrence was calculated from the time youths fulfilled criteria for recovery until they met full cri- teria for a new syndromal DSM mood episode. 0.6 0.4 0.2 0.0 1.0 0.8 CumulativeProportionRecurred 4003002001000 Time to Recurrence in Weeks Bipolar I disorder (N=207) Bipolar II disorder (N=21) Bipolar disorder not otherwise specified (N=108)
  6. 6. 800 Am J Psychiatry 166:7, July 2009 CHILDREN AND ADOLESCENTS WITH BIPOLAR SPECTRUM DISORDERS ajp.psychiatryonline.org ing more follow-up time with syndromal symptomatology, and bipolar disorder not otherwise specified and being non-Caucasian predicting more time with subsyndromal symptomatology, separate linear regressions for syndromal and subsyndromal symptomatology yielded similar results. Patients with chronic symptoms. In addition to ana- lyzing the percentage of time participants spent symp- tomatic (syndromal plus subsyndromal symptoms), we calculated chronicity, as measured by the percentage of participants who had syndromal and/or subsyndromal mood symptoms ≥75% of the follow-up time. Approxi- mately 38% of the participants, particularly those with bi- polar I (bipolar I > bipolar disorder not otherwise speci- fied, χ2=5.66, p=0.02), experienced chronic mood symptoms, with only 3% of participants meeting full syn- dromal criteria for mood episodes. Most of these chronic symptoms were mixed (46%), followed by depression (33.8%) and mania/hypomania (21%). Psychosis. Clinically relevant psychotic symptoms were defined as having a score of 3 (definitely present) for delu- sions and/or hallucinations on the Psychiatric Status Rating Scales. Overall, 16% of the participants experienced psy- chotic symptoms during the follow-up period. For these youths, psychotic symptoms were manifested during 17.1% of the follow-up time. Participants with bipolar I spent sig- nificantly more time with psychotic symptoms than did those with bipolar disorder not otherwise specified. Change in mood polarity. Shifts in mood polarity oc- curred a mean of 36.2 times (SD=46.9) during the entire fol- low-up period, or 12.1 times per year (SD=15.0) (Table 3). A change in mood polarity once per year or less was ob- served in 31.2% of the sample, five or more times per year in 51.1%, 10 times or more per year in 38.7%, and more than 20 times per year in 23.7%. Except for youths with bi- polar disorder not otherwise specified being more likely to have at least 10 changes in mood polarity per year com- pared to those with either bipolar I or II (p values ≤0.03, val- ues for Cohen’s ds ranging from 0.23 to 0.45), there were no other between-group differences. In a multiple linear re- gression, lower socioeconomic status (t=3.90, p=0.001), children with childhood onset (versus adolescents with adolescent onset, t=4.02, p=0.001), adolescents with child- hood onset (versus adolescents with adolescent-onset, t= 3.73, p=0.001), and presence of any comorbid disorder (t= 2.04, p=0.04) were significant predictors of having a greater number of changes in mood polarity per year. There were no other significant predictors or interactions. Conversion From Bipolar II to Bipolar I and From Bipolar Disorder Not Otherwise Specified to Bipolar I or II Of the 169 youths with bipolar II and bipolar disorder not otherwise specified, 61 (36.1%) converted to a differ- ent bipolar subtype over the follow-up period. Of these, 25% (7/28) with bipolar II converted to bipolar I, 19.9% (28/141) with bipolar disorder not otherwise specified converted to bipolar I, and 18.4% (26/141) with bipolar disorder not otherwise specified converted to bipolar II (38.3% of youths with bipolar disorder not otherwise spec- ified converted overall). TABLE 3. Weekly Symptomatic Status and Changes in Mood Polarity in 413 Youths With Bipolar Spectrum Disorders, by Bipolar Subtypea Symptomatology Total Sample (N=413) Bipolar I Disorder (N=244) Bipolar II Disorder (N=28) Bipolar Disorder Not Otherwise Specified (N=141) Analyses χ2 df p 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/ or hallucinations) 3.1 12.9 3.4a 12.1 5.5a,b 20.5 2.3b 12.3 11.99 2 0.002 Number of changes in mood polarity per yearb 12.1 15.0 11.0 13.8 10.3 16.3 14.3 16.7 2.46 2 0.3 N % N % N % N % ≤1 129 31.2 72 29.5 10 35.7 47 33.3 0.89 2 0.6 >5 211 51.1 123 50.4 10 35.7 78 55.3 3.70 2 0.2 >10 160 38.7 87 35.7a 7 25.0a 66 46.8b 7.07 2 0.03 >20 98 23.7 51 20.9 5 17.9 42 29.8 4.47 2 0.1 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.
  7. 7. Am J Psychiatry 166:7, July 2009 801 BIRMAHER, AXELSON, GOLDSTEIN, ET AL. ajp.psychiatryonline.org Discussion Corroborating prior COBY findings (4), this study showed that bipolar spectrum disorders in youths are episodic dis- orders characterized most often by subsyndromal episodes and less frequently by syndromal episodes, with mainly de- pressive and mixed symptoms and rapid mood changes. Survival analyses using the standard definitions of syn- dromal recovery and recurrence (based on DSM-IV and the literature) indicated that approximately 80% of youths with bipolar spectrum disorders achieved full recovery about 2.5 years after onset of their index episode. How- ever, 1.5 years after full recovery, approximately 60% of the participants had at least one syndromal recurrence. Com- pared to youths with bipolar disorder not otherwise spec- ified, those with bipolar I and II were more likely to recover but also to have a less durable recovery. During the entire follow-up period, one-third of the par- ticipants had at least one syndromal recurrence and 30% experienced more than two syndromal recurrences. Most of these syndromal recurrences were major depressions, followed by hypomanic, manic, and mixed episodes. In general, the polarity of the index episode predicted the po- larity of subsequent episodes. In addition to the analyses focusing only on recovery and recurrence of syndromal symptoms, week-by-week analyses provided a more in-depth clinical picture of the course of bipolar disorder, showing that distinct periods of full syndromal mood episodes exist in youths with bipolar spectrum disorders. However, these episodes are embed- ded in more prevailing and longer periods of subsyndro- mal mood symptomatology. Youths with bipolar spectrum disorders were symptomatic during 60% of the follow-up period, during which they spent about 2.5 times more time with subsyndromal than with syndromal symptoma- tology. Mixed/cycling and depressive symptoms ac- counted for the greatest proportion of time ill. In contrast, purely manic symptomatology, especially at the full syn- dromal level, was less common. Rapid mood changes were ubiquitous, and psychotic symptoms were relatively common, particularly in youths with bipolar I. Chronic symptoms, defined as having any type of symptoms dur- ing 75% or more of the follow-up period, were present in 38% of the participants. Almost all of these chronic symp- toms were subsyndromal and of the depressive type. The week-by-week analyses also shed light on the simi- larities and differences in the longitudinal patterns of symptom phenomenology of youths with bipolar I and II and bipolar disorder not otherwise specified. Bipolar I was manifested by more time with subsyndromal than with syndromal symptoms. Most of the syndromal time was characterized by mixed/cycling or depressive symptoms, and most of the subsyndromal time was with subsyndro- mal manic or mixed symptoms. Youths with bipolar II spent equal amounts of time in syndromal and subsyndro- mal states. The syndromal episodes were most commonly depression or mixed states, but there were no significant differences in the proportion of time spent with any type of subsyndromal symptoms. Finally, bipolar disorder not oth- erwise specified was mainly manifested by periods of sub- syndromal mixed symptoms, closely followed by periods of subsyndromal manic or depressive symptoms. Between-group comparisons provided preliminary vali- dation for the subtyping of bipolar disorder in youths. In general, in comparison with other subtypes, each bipolar subtype continued to show some category-specific symp- tomatology. For example, during follow-up, youths whose initial diagnosis was bipolar I showed more syndromal, mixed/rapid cycling, and manic/hypomanic symptoms than did those with bipolar disorder not otherwise speci- fied; youths with bipolar II spent more time in hypomania than did those with bipolar disorder not otherwise speci- fied and more time in depression than did those with bi- polar I and bipolar disorder not otherwise specified; and youths with bipolar disorder not otherwise specified spent significantly more time with subsyndromal symptoms than did those with bipolar I and II. However, there was some symptom overlap among the different bipolar sub- types, especially bipolar I and II. Moreover, 25% of youths with bipolar II converted to bipolar I, and 38% of those with bipolar disorder not otherwise specified converted to bipolar I and II. Although there were some differences in the demo- graphic and clinical factors associated with the outcome variables measured (recovery, time symptomatic, and changes in polarity), in general, early onset of bipolar dis- order, presence of comorbid disorders, family history of mood disorders (particularly mania/hypomania), low so- cioeconomic status, and non-Caucasian race were associ- ated with worse outcome. Long duration of illness was also associated with a lower likelihood of recovery, with each year of illness decreasing the likelihood of recovery by 20%. Before continuing the discussion of COBY’s findings, it is important to note the limitations of this study. First, de- spite efforts to obtain precise information, the data col- lected through the Longitudinal Interval Follow-Up Evalu- ation is subject to retrospective recall bias. Although it appears that this instrument has adequate psychometric properties (1, 4, 12), further studies using the methods de- scribed by Warshaw et al. (12) and including blind inter- viewers are warranted. Second, although COBY used the standard definitions of course for recovery and recurrence (1, 3, 18), the rates and duration of the mood episodes may change according to the duration criteria and symptom threshold severity chosen. Third, the results pertaining to youths with bipolar II should be considered tentative given the relatively small size of this group. However, across all bipolar subtypes, after depression most syndro- mal recurrences were hypomanias. Finally, as most partic- ipants were Caucasian and were recruited primarily from outpatient and, to a lesser extent, inpatient settings, the generalizability of the observations to other populations
  8. 8. 802 Am J Psychiatry 166:7, July 2009 CHILDREN AND ADOLESCENTS WITH BIPOLAR SPECTRUM DISORDERS ajp.psychiatryonline.org remains uncertain. Nevertheless, nonreferred adolescents with bipolar disorder have been shown to have a similar course and high morbidity (5). Despite methodological differences, all existing studies of the course of bipolar disorder in youths, regardless of country and source of ascertainment, show that the likeli- hood of recovery from the index episode is high (1–4). However, as with adult populations, despite the high re- covery rate, the rates of recurrence, persistence of subsyn- dromal clinical morbidity, and rapid and frequent changes in mood polarity are also high, and most syndromal and subsyndromal recurrences are depressions (16, 19–23). It does appear that the polarity of the index episode predicts the polarity of the subsequent episodes (21, 24–28), which suggests the possibility of using specific psychosocial and pharmacological treatments based on the polarity of the index episode. The results of this and other emerging pediatric studies suggest strong general similarities in the longitudinal course of bipolar disorder in youths and adults, which is mainly manifested by subsyndromal symptomatology and rapid mood changes (1–4, 29). However, there is evi- dence that very early onset confers greater liability for a more chronic and fluctuating course, mixed/cycling epi- sodes, high rates of comorbid disorders, and increased rates of mood disorders in families (1, 3, 30–32). Converg- ing with these accounts are reports indicating that adults whose onset of bipolar disorder dates to childhood have a more severe and chronic course, lower quality of life, and more episodes, changes in mood polarity, suicidality, and comorbidity (33–35). Comparable with other findings in the literature (1–4, 6), we found that childhood-onset bipolar disorder, comorbid disorders, positive family history for mood disorders, and low socioeconomic status were associated with poorer out- come. Moreover, the probability of recovery was inversely related to duration of illness, which further underscores the importance of early detection of illness and rapid im- plementation of stabilizing treatments. Such efforts may be of even greater urgency for youths with bipolar disorder who have risk factors associated with poorer outcome. Similar to findings in the literature on major depression (36), it appears that there are some differences in the fac- tors associated with the various indices of clinical out- come (recovery, recurrence, and amount of time symp- tomatic). Moreover, as the polarity of the index episode was shown to convey different prognostic characteristics, it may be that these observations will be informative to clinical practice. For example, since youths with depres- sion were seen to have more depressive recurrences, they may require more aggressive and specific therapies to re- duce the risk of future depressive episodes. To our knowledge, COBY is the first naturalistic, pro- spective study of this affective subtype in youths—an im- portant avenue of research given the modal age of onset of bipolar II illness during adolescence (18, 27, 37). Consis- tent with adult data on high levels of morbidity associated with this subtype, youths with bipolar II had a greater overall risk of recurrence and more depressive morbidity compared to youths with bipolar I, and had rates of nonaf- fective comorbidity, suicidality, nonsuicidal self-injurious behaviors, functional impairment, and family history of bipolar and other mood disorders comparable to those with bipolar I (6, 7, 32, 38–40). Also, bipolar II in youths ap- pears to be a far less stable phenotype than in adults; in this cohort, 25% of the bipolar II youths converted to bipo- lar I, a rate higher than that reported in adult studies (41). Since this disorder is mainly characterized by episodes of syndromal and subsyndromal depression across the lifespan, it is well appreciated that periods of hypomania can be misconstrued as normal fluctuations in mood or as erratic behavior, and perhaps more so in adolescents (27, 42), resulting in a high risk of misclassification as recurrent unipolar depression or other, nonaffective disorders. Bipolar disorder not otherwise specified is character- ized by rates of comorbidity, suicidality, functional impair- ment (except hospitalizations), and family history of mood disorders equivalent to those in youths with bipolar I and II (6, 7, 32, 38–40). These findings, together with the high rates of conversion to bipolar I or II, provide prelimi- nary validation of its nosological affinity with bipolar I and II disorder. It should be emphasized, however, that our classification relied on the presence of an affective pheno- type that differed from bipolar I or II due to failure to meet the DSM-IV duration requirements for these subtypes. Thus, our findings are in accord with studies in the adult literature (18, 42, 43) emphasizing the existence of clini- cally relevant episodes of mania/hypomania that last for less time than required by DSM criteria. These episodes are often overlooked because of the predominance of syn- dromal depression and subsyndromal manic/mixed symptoms of short duration in its expression. Results from COBY suggest that bipolar disorder not otherwise speci- fied is an episodic illness, albeit one that often comprises subsyndromal episodes that should be considered distinct from the symptomatology of youths with behavior disor- ders and “severe mood dysregulation” (44). In summary, although distinct episodes of full syndro- mal mood symptomatology as well as durable periods of euthymia can be identified in youths with bipolar disor- der, the course of bipolar spectrum disorders in children and adolescents is predominantly characterized by sub- syndromal and, much less frequently, syndromal epi- sodes. Rapid mood changes are evident during these epi- sodes, which are mainly of depressive and mixed polarity. During follow-up each bipolar subtype showed some dis- tinct clinical characteristics and course, but there was overlap in their symptoms and substantial conversion from bipolar II and bipolar disorder not otherwise speci- fied into other bipolar subtypes. The course of bipolar dis- order, the relative infrequency of syndromal DSM manic episodes, the effects of development in symptom manifes-
  9. 9. Am J Psychiatry 166:7, July 2009 803 BIRMAHER, AXELSON, GOLDSTEIN, ET AL. ajp.psychiatryonline.org tation, and the high prevalence of comorbid disorders may account, at least in part, for the difficulties in recog- nizing and managing this illness in youths. The recur- rence, chronicity, and psychosocial morbidity associated with this illness in critical developmental stages call for its prompt recognition and the development of more effica- cious treatments, particularly since each year of illness ap- pears to decrease the likelihood of recovery. Received Oct. 23, 2008; revisions received Dec. 21, 2008, and Feb. 10, 2009; accepted Feb. 17, 2009 (doi: 10.1176/appi.ajp.2009.08101569). From the Department of Psychiatry, Western Psychiatric Institute and Clinic, University of Pittsburgh Medical Center, Pittsburgh; Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Med- icine, University of California at Los Angeles; Department of Psychiatry and Human Behavior, Warren Alpert Medical School, Brown University, Providence, R.I.; Department of Statistics, University of Pittsburgh. Ad- dress correspondence and reprint requests to Dr. Birmaher, Western Psychiatric Institute and Clinic, 3811 O’Hara St., Pittsburgh, PA 15213; birmaherb@upmc.edu (e-mail). Dr. Birmaher has participated in forums sponsored by Forest, Shire, Jazz Pharmaceuticals, Solvay, and Abcomm and receives royalties from Random House and Lippincott Williams & Wilkins. Dr. Keller has received research support from, served as consultant to, or served on speakers bureaus or advisory boards for Abbott, Bristol-Myers Squibb, CENEREX, Cephalon, Cypress Bioscience, Cyberonics, Forest, Janssen, JDS, Medtronic, Neuronetics, Novartis, Organon, Pfizer, Roche, Solvay, and Wyeth. All other authors report no competing in- terests. Supported by NIMH grants MH59929 (to Dr. Birmaher), MH59977 (to Dr. Strober), and MH59691 (to Dr. Keller). The authors thank Carol Kostek for her assistance with manuscript preparation and Shelli Avenevoli, Ph.D., at NIMH, for her support and guidance. References 1. DelBello MP, Hanseman D, Adler CM, Fleck DE, Strakowski SM: Twelve-month outcome of adolescents with bipolar disorder following first hospitalization for a manic or mixed episode. Am J Psychiatry 2007; 164:582–590 2. Birmaher B: Longitudinal course of pediatric bipolar disorder (editorial). Am J Psychiatry 2007; 164:537–539 3. 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