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Original Article |

Clinical Course of Children and Adolescents With Bipolar Spectrum Disorders FREE

Boris Birmaher, MD; David Axelson, MD; Michael Strober, PhD; Mary Kay Gill, MSN; Sylvia Valeri, PhD; Laurel Chiappetta, MS; Neal Ryan, MD; Henrietta Leonard, MD; Jeffrey Hunt, MD; Satish Iyengar, PhD; Martin Keller, MD
[+] Author Affiliations

Author Affiliations: Department of Psychiatry, Western Psychiatric Institute and Clinic, University of Pittsburgh Medical Center (Drs Birmaher, Axelson, and Ryan and Mss Gill and Chiappetta), and Department of Statistics, University of Pittsburgh (Dr Iyengar), Pittsburgh, Pa; Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine, University of California at Los Angeles (Dr Strober); and Department of Psychiatry and Butler Hospital, Brown University School of Medicine, Providence, RI (Drs Valeri, Leonard, Hunt, and Keller).


Arch Gen Psychiatry. 2006;63(2):175-183. doi:10.1001/archpsyc.63.2.175.
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Published online

Context  Despite the high morbidity associated with bipolar disorder (BP), few studies have prospectively studied the course of this illness in youth.

Objective  To assess the longitudinal course of BP spectrum disorders (BP-I, BP-II, and not otherwise specified [BP-NOS]) in children and adolescents.

Design  Subjects were interviewed, on average, every 9 months for an average of 2 years using the Longitudinal Interval Follow-up Evaluation.

Setting  Outpatient and inpatient units at 3 university centers.

Participants  Two hundred sixty-three children and adolescents (mean age, 13 years) with BP-I (n = 152), BP-II (n = 19), and BP-NOS (n = 92).

Main Outcome Measures  Rates of recovery and recurrence, weeks with syndromal or subsyndromal mood symptoms, changes in symptoms and polarity, and predictors of outcome.

Results  Approximately 70% of subjects with BP recovered from their index episode, and 50% had at least 1 syndromal recurrence, particularly depressive episodes. Analyses of weekly mood symptoms showed that 60% of the follow-up time, subjects had syndromal or subsyndromal symptoms with numerous changes in symptoms and shifts of polarity, and 3% of the time, psychosis. Twenty percent of BP-II subjects converted to BP-I, and 25% of BP-NOS subjects converted to BP-I or BP-II. Early-onset BP, BP-NOS, long duration of mood symptoms, low socioeconomic status, and psychosis were associated with poorer outcomes and rapid mood changes. Secondary analyses comparing BP-I youths with BP-I adults showed that youths significantly more time symptomatic and had more mixed/cycling episodes, mood symptom changes, and polarity switches.

Conclusions  Youths with BP spectrum disorders showed a continuum of BP symptom severity from subsyndromal to full syndromal with frequent mood fluctuations. Results of this study provide preliminary validation for BP-NOS.

Figures in this Article

There has been steadily growing interest in the clinical and public health implications of bipolar disorder (BP) affecting children and adolescents. Current literature depicts the disease as devastating with substantial impairment across psychosocial domains, high risk of suicide, psychosis, significant familial aggregation, and protracted illness course in which the classically described cycles of disease followed by well periods are rarely observed.116

To date, few prospective studies, including clinical samples8,1114 and a single community study,9,10 have investigated the outcome of pediatric BP. The duration of these studies varies from 1 to 5 years, with most cohorts showing 70% to 100% recovery with high rates of recurrences (≤80%), hospitalizations, psychosis, suicide attempts and completion, and poor psychosocial functioning. Retrospective studies that have followed up youth with BP for longer periods have shown similar findings.4,5,1520

At present, it is not known if onset of BP early in life is characterized by similar or fundamentally different long-term patterns of disease progression compared with adult-onset BP.21 The pediatric samples followed up have been of small to modest sizes, and subjects have been followed up infrequently or for relatively brief periods. Other pediatric studies have been retrospective in nature or have relied on medical record reviews for depicting the follow-up course rather than direct clinical interviews. So far, no study has prospectively collected syndromal and subsyndromal course data on children and adolescents representing the full spectrum of BP phenotypes, in particular BP not otherwise specified (BP-NOS).22

This report describes the early clinical course and some relevant predictors of outcome of children and adolescents with bipolar I disorder (BP-I), BP-II, and BP-NOS recruited as part of a multisite (University of Pittsburgh, Brown University, and University of California at Los Angeles), collaborative study funded by the National Institute of Mental Health, the Course and Outcome of Bipolar Illness in Youth (COBY). The COBY study constitutes the largest pediatric BP cohort study to date, and it is the first prospective naturalistic study involving children and adolescents with BP spectrum disorders (BP-I, BP-II, and BP-NOS).

Subsequent reports will describe in more detail the clinical picture of children and adolescents with BP spectrum disorders, psychosocial course, and effects of other potential predictors of outcome such as suicidal behaviors, comorbid disorders, family psychiatric history, and treatment.

SUBJECTS

Children and adolescents aged 7 to 17 years 11 months (mean ± SD age, 13.0 ± 3.1 years) whose primary diagnoses were DSM-IV23 BP-I or BP-II or an operationalized definition of BP-NOS were enrolled in the COBY study. Because the DSM-IV definition of BP-NOS is vague, BP-NOS was defined as the presence of clinically relevant BP symptoms that did not fulfill the DSM-IV criteria for BP-I or BP-II. In addition, subjects were required to have a minimum of elated mood plus 2 associated DSM-IV symptoms or irritable mood plus 3 DSM-IV associated symptoms, along with a change in the level of functioning, duration of a minimum of 4 hours within a 24-hour period, and at least 4 cumulative lifetime days meeting the criteria.

Subjects with current or lifetime diagnoses of schizophrenia, mental retardation, autism, and mood disorders secondary to substance abuse, medical conditions, or use of medications were excluded.

Subjects were recruited from consecutive admissions to outpatient clinics (65%), inpatient units (16%), advertisement (11%), and referrals from other physicians (8%) and were enrolled independent of current BP state or treatment status.

The analyses presented in this report are based on the prospective assessment of psychiatric symptoms for 263 subjects, including 151 (57%) with BP-I, 20 (8%) with BP-II, and 92 (35%) with BP-NOS who had at least 1 follow-up assessment. To date, these subjects have been prospectively interviewed every 35.5 weeks (SD, 8.5 weeks) for a mean ± SD of 94.8 ± 51.5 weeks.

As depicted in Table 1, at intake subjects with BP-I and BP-NOS were slightly younger than those with BP-II, and more BP-NOS subjects were prepubertal (all comparisons, P≤.05). Fewer BP-I subjects were living with both biological parents than BP-II and NOS subjects. Subjects with BP-II had the onset of their mood disorders significantly later and had significantly lower rates of comorbid attention-deficit/hyperactivity disorder than subjects with BP-I and BP-II (P≤.05). Subjects with BP-I had significantly more lifetime psychosis than those with BP-NOS (P = .002). There were no other differences among the 3 BP subtypes with regard to demographics or clinical characteristics, and there were no differences among groups regarding family history of mood disorders in first- and second-degree relatives.

Table Graphic Jump LocationTable 1. Demographic and Clinical Characteristics Among Subjects With BP-I, BP-II, and BP-NOS*

At present, the subject retention rate is 95%. Subjects who have dropped out from the study (n = 18) were significantly older (t = 3.0 [P = .003]) and non-Caucasian (χ2 = 7.9 [P = .005]), had higher rates of anxiety disorders (χ2 = 5.8 [P = .02]), and more frequently lived in a situation other than with both natural parents (χ2 = 5.3 [P = .02]) when compared with subjects who continued in the study.

PROCEDURES

Each university's institutional review board approved the study. Assent was obtained from children and adolescents and consent from parents. We directly interviewed children and parents (about their children) for the presence of current and lifetime nonmood psychiatric disorders using the Schedule for Affective Disorders and Schizophrenia for School Age Children–Present and Lifetime Version (K-SADS-PL)24 and for the presence of mania and depression with the K-SADS–Mania Rating Scale25 and the depression section of the K-SADS-PL,26 respectively.

Longitudinal changes in psychiatric symptoms, functioning, and treatment exposure since the previous evaluation were assessed using the Longitudinal Interval Follow-up Evaluation (LIFE).27 The LIFE was administered to adolescents and parents separately. Because younger children often have problems timing their symptoms, they were interviewed with their parents. Any discrepancies between the informants' responses were discussed, and a summary score based on all available information was determined. The LIFE9,10,2729 evaluates the course of symptoms by identifying change points, frequently anchored by memorable dates for the subject (eg, holidays and beginning of school). The severity of ongoing symptoms, onset of new symptoms, and episode polarity for BP since the last appointment are tracked on a week-by-week basis using the LIFE Psychiatric Status Rating (PSR) scale. For DSM-IV mood disorders, the PSR scores range from 1 for no symptoms, to 2 to 4 for varying levels of subthreshold symptoms and impairment, to 5 or 6 for full criteria with different degrees of severity or impairment. Comorbid disorders and psychosis are also rated on a weekly basis on a 3-point scale of 1 to 3, where 3 indicates threshold symptoms. Family history of mood disorders was ascertained using the Family History Screen.30

The Petersen Pubertal Developmental Scale31 was used to evaluate pubertal stages, which were categorized into prepubertal (equivalent to Tanner32,33 stage I of sexual development), midpubertal (Tanner stages II and III), and postpubertal (Tanner stages IV and V). Subjects 10 years or older completed the Petersen Pubertal Developmental Scale by themselves. Subjects aged 7 to 9 years completed the Petersen Pubertal Developmental Scale with their parents' assistance, and parents completed the form for those younger than 7 years. Socioeconomic status (SES) was ascertained using the 4-factor Hollingshead Scale.34

All assessments were completed by research staff trained to reliably administer the interviews and presented to child psychiatrists/psychologists who confirmed the diagnoses. When necessary, subjects' medical records were reviewed. The overall K-SADS kappas for psychiatric disorders were 0.8 or more. The intraclass correlation coefficients for the K-SADS Mania Rating Scale and the depression section of the K-SADS-PL were 0.95 or more. The LIFE intraclass correlations for mood disorders were 0.80 or more.

DEFINITIONS OF COURSE OF ILLNESS

As described in the literature,28,35,36 recovery from a mood episode required 8 consecutive weeks with a PSR score of 2 or less (minimal or no symptoms). A recurrence (new episode) required a PSR score of 5 or more, with durations of 1 week for mania/hypomania and 2 weeks for depression. Rapid cycling and mixed episodes were defined as in the DSM-IV.

STATISTICAL ANALYSES

Differences between groups were analyzed using standard parametric and nonparametric univariate tests. The index episode was defined as the current or most recent episode from the date of intake. Because the index episode could have started before the subjects were recruited into the study, time to recovery was calculated from the onset of the index episode to ascertain the real duration of illness. Therefore, for some subjects the duration of episode exceeded the length of prospective follow-up. Time to recurrence was calculated from the time subjects fulfilled criteria for recovery until they met full criteria for a new mood episode. Cumulative rates of recovery and recurrence were analyzed using survival analytical methods37 stratifying subjects by BP subtype.

About 14% of the sample had their acute episode offset and recovered before intake (mean time, 44.5 ± 53.4 weeks). Analyses of the rates of recovery and recurrence with or without these subjects yielded similar results. Therefore, every subject, regardless of his or her episode status at the intake assessment, was included in this analysis.

To provide a more complete picture of the longitudinal course of BP in youth, the percentages of follow-up weeks spent asymptomatic or symptomatic in the different mood symptom status categories (eg, mania, mixed, and subsyndromal symptoms) were computed based on the PSR ratings for each subject. To compare the COBY's BP-I data with those of a recent adult BP-I study28,29 that used comparable methods, changes in symptom status and polarity were defined and analyzed similarly to those used in the adult study. Symptom status was defined as the change in the weekly PSR ratings in levels of depressive and/or manic/hypomanic symptoms or change from/to the asymptomatic status. Change in polarity was defined as a switch between depression (PSR, ≥3) and mania/hypomania (PSR, ≥3) or vice versa with or without intervening weeks at the asymptomatic status. For these last 2 analyses, similar to those of Judd et al,28,29 weeks with mixed symptoms of depression and mania/hypomania were included together.

For all of these analyses, the effects of demographic variables, pubertal status, subtype of BP, lifetime psychosis, age of onset of BP symptoms (depression and/or mania/hypomania), and duration of illness were evaluated. Interactions among significant predictors in the models were also examined. These variables were examined univariately, and those related to the outcome of interest were included in the regression models. To assess the effects of age on the child's outcome, the sample was dichotomized into children younger than 12 years and those 12 years or older. However, because some of the children 12 years and older had the onset of their illness when they were younger, the analyses for the effects of age and age of onset were evaluated in the following way: (1) children younger than 12 years, (2) adolescents 12 years or older with onset of BP at younger than 12 years, and (3) adolescents 12 years or older with onset of BP at 12 years or older. Models were run separately for pubertal status and the age/age of BP onset variable owing to high colinearity. For the survival analyses, the effects of these variables were evaluated using Cox proportional hazards regressions.38 For the weekly symptomatic status (ie, change in symptoms status and polarity), the same predictors were examined using linear regression models.

Unless otherwise indicated, all values are reported as mean ± SD. All P values are based on 2-tailed tests with α = .05.

RECOVERY AND RECURRENCE BY BP SUBTYPE
Recovery

As depicted in Figure 1 and Table 2, overall 68% of subjects recovered from their index episode a median of 78 weeks after the onset of the episode. There was no significant difference in rates of recovery among the 3 BP subgroups, but subjects with BP-NOS had a significantly longer time to recovery than subjects with BP-I and BP-II (all comparisons, P≤.05).

Place holder to copy figure label and caption
Figure 1.

Recovery stratified by bipolar subtype. The index episode was defined as the most recent or current episode from the date 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 exceeded the length of prospective follow-up. BP-I indicates bipolar I disorder; BP-II, bipolar II disorder; BP-NOS, bipolar disorder not otherwise specified.

Graphic Jump Location
Table Graphic Jump LocationTable 2. Summary of Recovery and Recurrence by BP Subtype*

Cox proportional hazards regressions showed that compared with adolescents, subjects with childhood onset were 1.7 times (95% confidence interval [CI], 1.19-2.56) less likely than those with early BP onset and 1.9 times (95% CI, 1.3-2.8) less likely than those with late onset to recover. With every unit decrease in SES, subjects had a 25% lower likelihood of recovery (hazard ratio, 1.25; 95% CI, 1.10-1.43). Finally, with longer duration of BP (per year), subjects had a 10% lower likelihood of recovery (hazard ratio, 0.90; 95% CI, 0.84-0.96). Prepubertal subjects were 1.7 times (95% CI, 1.06-2.65) less likely than midpubertal subjects and 1.9 times (95% CI, 1.27-2.85) less likely than late pubertal subjects to recover. Those with BP-NOS were 2.0 times (95% CI, 1.43-2.88) less likely than BP-I subjects and 1.9 times (95% CI, 1.05-3.52) less likely than BP-II subjects to recover. No other significant predictors or interactions were found.

Recurrence

As depicted in Figure 2 and Table 2, overall 56% of subjects had at least 1 recurrence a median of 61.0 weeks after recovery of the index episode. Subjects with BP-II had higher rates of recurrence than subjects with BP-NOS and subjects with BP-NOS had significantly longer time to recurrence than those with BP-I and BP-II (all comparisons, P≤.05).

Place holder to copy figure label and caption
Figure 2.

Recurrence stratified by bipolar subtype. Time to recurrence was calculated from the time subjects fulfilled criteria for recovery until they met full criteria for a new mood episode. Abbreviations are explained in the legend to Figure 1.

Graphic Jump Location

Cox proportional hazards regressions showed that BP-I subjects were 1.7 times (95% CI, 1.06-2.67) and BP-II subjects were 2.7 times (95% CI, 1.35-5.31) more likely to have a recurrence than those with BP-NOS. Subjects with low SES had a 20% higher likelihood of recurrence (with every unit of decrease in SES) (95% CI, 0.67-0.95). No other significant predictors or interactions were found.

RECURRENCE DURING FOLLOW-UP

Subjects had a mean ± SD of 1.5 ± 0.9 syndromal recurrences. After controlling for differences in the length of the follow-up, there were no significant differences in the number of syndromal recurrences among subjects with BP-I, BP-II, and BP-NOS. Most of these recurrences were major depressive episodes (57.5%), followed by hypomania (24.2%), mania (13.7%), and mixed (4.6%). There were no significant differences in the polarity of the recurrences among subjects with BP-I, BP-II, and BP-NOS.

WEEKLY MOOD SYMPTOMATIC STATUS BY BP SUBTYPE

As depicted in Table 3, on average, subjects spent 39.7% of the follow-up time without clinically significant mood symptoms, 22.4% of the time in a DSM-IV syndromal episode, 37.9% of the time with subsyndromal symptoms, and 3.1% of the time with clinically significant symptoms of psychosis (PSR score for delusion and/or hallucinations, 3). Within the syndromal symptoms, subjects with BP-I spent significantly more weeks with syndromal mania and mixed symptoms than those with BP-NOS, and subjects with BP-II spent significantly more time with depressive symptoms than those with BP-I and BP-II (all comparisons, P≤.001). Within the subsyndromal symptoms, BP-NOS subjects spent significantly more weeks with subsyndromal mania and mixed symptoms compared with BP-I subjects, and BP-II subjects spent significantly more time with subsyndromal depression than BP-I and BP-NOS subjects (all comparisons, P≤.05).

Table Graphic Jump LocationTable 3. Weekly Symptomatic Status by Bipolar Subtype*

Linear regression models showed that lifetime psychosis (t = 2.96 [P = .003]) and the interaction between childhood onset of BP and low SES (t = 2.38 [P = .02]) were significant predictors of more time spent with any mood symptoms. In the same model, the main effects of low SES and childhood onset of BP (vs adolescents with late onset) remained marginally significant predictors of time spent with any mood symptoms (all comparisons, P≤.15).

Diagnosis of BP-I (vs BP-NOS, t = 2.57 [P = .01]), lower SES (t = 2.98 [P = .003]), lifetime psychosis (t = 2.78 [P = .006]), and female sex (t = 1.99 [P = .05]) were found to be significant predictors of more follow-up time spent with syndromal manic/major depressive disorder symptoms (F = 6.63 [P<.001]). There were no significant interactions.

Diagnosis of BP-NOS (vs BP-I, t = 3.56 [P<.001]; vs BP-II, t = 2.38 [P = .02]), lower SES (t = 2.74 [P = .007]), and childhood onset of BP (vs adolescents with late onset, t = 2.67 [P = .008]) were found to be significant predictors of follow-up time spent with subsyndromal mood symptoms. There were no significant interactions.

CHANGE IN SYMPTOM STATUS

Subjects experienced a mean ± SD of 34.1 ± 32.2 changes in symptom status during the entire follow-up period, or 19.8 ± 16.6 per year. Approximately 6% of the sample had 1 or fewer changes in symptom status per year. Eighty-six percent of the sample changed symptom status more than 3 times per year, 78% changed more than 5 times per year, 62% changed more than 10 times per year, and 40% changed more than 20 times per year. There was a significant difference between the BP groups in the number of total symptom changes (Kruskal-Wallis χ2 = 7.14 [P = .03]), with BP-NOS subjects showing more symptom changes than BP-I and BP-II subjects (all comparisons, P≤.05). Linear regressions show low SES (t = 2.13 [P = .03]), longer duration of mood disorder (t = 2.33 [P = .02]), lifetime psychosis (t = 3.71 [P<.001]), and BP-NOS diagnosis (vs BP-I, t = 3.15 [P = .002]) as significant predictors of greater number of changes in symptom status per year (F = 7.62 [P<.001]). There were no significant interactions.

CHANGE IN POLARITY

Shifts in polarity occurred at a mean ± SD of 26.1 ± 30.7 times during the entire follow-up period or 15.7 ± 17.0 times per year. About 19% of patients changed polarity once per year or less, 61% changed 5 or more times per year, 47% changed more than 10 times per year, and 30% changed more than 20 times per year. There were no differences in the number of changes in polarity among BP-I, BP-II, and BP-NOS subjects. Lower SES (t = 2.84 [P = .005]), lifetime psychosis (t = 3.73 [P<.001]), and BP-NOS diagnosis (vs BP-I, t = 2.88 [P = .004]) were significant predictors of greater number of changes in polarity per year (F = 8.14 [P<.001]). There were no significant interactions.

CONVERSION FROM BP-II TO BP-I AND FROM BP-NOS TO BP-I OR BP-II

During follow-up, 4 (21%) of the 19 BP-II subjects experienced conversion to BP-I; 18 (20%) of the 92 BP-NOS subjects, to BP-I; and 9 (10%) of the 92 BP-NOS subjects, to BP-II. Increased rates of conversion were associated with female sex (odds ratio, 3.2; 95% CI, 1.33-7.50) and long duration of illness (odds ratio, 0.8; 95% CI, 0.68-0.95). There were no other significant predictors of conversion.

To our knowledge, this is the first report to describe the psychopathological course of each of the major clinical phenotypes of BP among children and adolescents, and it is the largest cohort of pediatric subjects with BP described in the literature to date. The general findings highlight the substantial morbidity of the illness in this age group, including early age of first onset of mood disturbance, long duration, fluctuating course, high familial loading for mood and other psychiatric disorders, and high rates of comorbid disorders, particularly attention-deficit/hyperactivity disorder, disruptive behavior, and anxiety disorders. Although recovery from the index episode was observed in approximately two thirds of subjects, half of them had at least 1 full syndromal recurrence. Subjects with BP-I and BP-II recovered from their index episode and had recurrence more frequently than those with BP-NOS. In contrast, subjects with BP-NOS had a more protracted illness, but once they recovered from their index episode, they took a longer time to recur than those with BP-I and BP-II. On average, subjects had 1.5 syndromal recurrences per year, particularly depressive episodes. Complementing this information, analyses of weekly mood symptoms ascertained through the LIFE showed that subjects were symptomatic approximately 60% of the follow-up time, with about 22% of the time in full syndromal episodes and 38% of the time with subsyndromal symptoms. Subjects with BP-I had more syndromal manic/hypomanic and mixed episodes than those with BP-NOS, and subjects with BP-II had more syndromal and subsyndromal depression that those with BP-I and BP-NOS. In contrast, subjects with BP-NOS showed more subsyndromal symptoms. During the follow-up, subjects with all types of BP, and particularly those with BP-NOS, with early onset or psychosis showed numerous changes in symptoms and shifts of polarity. Approximately 20% of subjects who had an intake diagnosis of BP-II experienced conversion to BP-I, and 25% of the BP-NOS subjects experienced conversion to BP-I or BP-II. Overall, subjects whose illness started early in life or who had longer duration of illness, BP-NOS, low SES, or psychotic symptoms had worse outcome.

Several limitations of the study deserve comment. As with any prospective interview study in which subjects are asked to recall mood symptoms since the most recent assessment, the information gathered is subject to multiple sources of unreliability. Our efforts to maximize the accuracy of the information obtained included attempts to interview subjects every 6 months using well-defined anchor points to assist them with recall of critical events of importance during the interview period. This method has shown superior reliability in the COBY and other studies.9,10,2729 Because most subjects were Caucasian and were recruited primarily from outpatient and inpatient settings, the results of this study cannot be generalized to other populations. Nevertheless, a community study using the LIFE9,10 also attested to the chronicity and high morbidity of BP spectrum disorders in youth. In addition, results pertaining to subjects with BP-II should be considered tentative because the BP-II sample was small. The definition of change in polarity used in this study and that of Judd et al28 was not meant to reflect the DSM-IV classification of rapid cycling and may have inflated the rate of shifts in polarity. However, to compare the COBY's BP-I data with the adult data, it was necessary to use the same definition. Finally, the observed outcomes were in the context of naturalistically applied treatment. However, the COBY's findings of recurrent and fluctuating episodes between mild and severe mood symptoms are similar to those reported by Kraepelin39 in patients with BP before pharmacological treatments were available.

Comparable to the extant pediatric BP literature,515 the COBY subjects first manifested emergent signs of mood disturbance early in life and had frequent comorbid psychiatric disorders, psychosis, and high familial loading for mood and other psychiatric disorders. Also in agreement with other studies,814 most subjects included in this study recovered from their index episode, but most had at least 1 recurrence, particularly episodes of depression. However, the rates of recovery and recurrence of syndromal episodes alone did not entirely depict the degree of morbidity reflected in the longitudinal course of BP in youth. Two thirds of the time, the COBY subjects experienced significant mood symptoms and, as reported in other pediatric studies,1,6,8 showed numerous changes in the intensity of mood symptoms and shifts in polarity. In this regard, our results are also comparable with those of recent studies of adults with BP-I and BP-II in which polyphasic episodes and interepisodic symptoms of subthreshold intensity are frequent.28,29,3949 Nevertheless, it appears that there are developmental differences in the course of BP between children and adults.1,6,8,40,50,51 To address this issue, using the same definitions of outcome proposed by Judd et al28 and after consulting with their statisticians, we compared the COBY BP-I youth with adults with BP-I (Table 4). The COBY subjects with BP-I spent significantly more time symptomatic and had more mixed/cycling episodes, mood symptom changes, and polarity switches than adults with BP-I.28 Thus, across the age span and especially in youth, BP usually follows an ongoing changeable and sinuous course, with patients having a wide spectrum of mood symptoms ranging from mild to severe depression to mania and/or hypomania. These results substantiate what Kraepelin39 and other investigators47 and clinicians have observed and explain, at least in part, the difficulties encountered when treating subjects with BP spectrum disorders. Furthermore, it is likely that the very rapid fluctuation in mood symptoms combined with the developmental issues influencing the clinical picture of BP in youth, the difficulties children and sometimes adolescents have verbalizing their emotions, and the high rates of comorbid disorders account for the complexity and current controversies in diagnosing BP in children and adolescents.

Table Graphic Jump LocationTable 4. Comparison of Weekly Symptom Status, Change in Symptom Status and Polarity, and Time With Psychosis Between Youth and Adults With BP-I*

Although for approximately 40% of the follow-up time, the COBY subjects were free of significant mood symptoms, a substantial proportion had ongoing comorbid psychiatric disorders. Thus, unless subjects undergo prospective evaluation, accurate description of the course of BP in youth may be difficult given the phenotypic overlap between BP and certain specific symptoms of comorbid disorders such as attention-deficit/hyperactivity disorder, with which it frequently co-occurs, and may give the appearance that BP does not cycle through episodes over time.

Youth with BP showed high lifetime rates of psychosis.5,8,9 As described in the literature,5,47,52,53 the presence of psychosis was consistently associated with poor prognosis, indicating the need for intensive and prompt treatment of this symptom.

In contrast to reports in the literature of adult BP,47,49 the prevalence of substance abuse by subjects in this study was low. However, most subjects included in our study had not yet reached the age of high risk for development of substance abuse. Therefore, this finding emphasizes the importance of prompt treatment of youth with BP before they begin to use substances that could complicate the management of their mood disorder and worsen their long-term prognosis.47,49

The rate of conversion from BP-II to BP-I found in the COBY study is higher than the cumulative rate of conversion reported in the adult literature,54 possibly suggesting that BP-II is less developmentally stable in the pediatric age group. At this time, there are to our knowledge no other published longitudinal studies of children and adolescents with BP-II with which to compare the COBY's findings. Likewise, this is the first study in the BP literature suggesting the relative instability of the BP-NOS phenotype, as approximately one third of BP-NOS subjects within the period of follow-up experienced conversion to BP-I or BP-II. In contrast, another study followed up a community sample of 54 adolescents who had subsyndromal BP symptoms and found an increased risk for major depression but not for BP.10 However, compared with the COBY's definition of BP-NOS, this later study defined subsyndromal BP less stringently as “a distinct period of abnormally and persistently elevated, expansive, or irritable mood”10(p282) only, suggesting possibly less liability for full BP than captured by the COBY's more restrictive definition. Furthermore, the presence of only 1 symptom, particularly irritability, does not necessarily mean that these adolescents had BP or that BP will develop.10,55

As has been reported by others,5,8,40,50,51 subjects in whom BP symptoms developed during their early childhood showed lower rates of recovery, more time in mixed/rapid cycling episodes, and more symptom and polarity changes than those whose illness started later. Also, comparable with recent adult BP studies,53,56 the results of the COBY study consistently showed that BP subjects with low SES had worse prognosis. Future studies will evaluate possible factors (eg, exposure to negative life events, lack of or poor adherence to treatment, and increased family psychopathologic characteristics) that may account for this finding.

The longitudinal course of children and adolescents with BP-NOS presented herein, together with the findings that these subjects have comparable rates of comorbidity and family history for mood disorders when compared with subjects with BP-I and BP-II, provide initial validation of the BP-NOS category as defined in the COBY. Furthermore, these results support the recommendation of the National Institute of Mental Health Consensus Roundtable22 and others1,6,48,57,58 to include children and adolescents with significant subsyndromal BP symptoms and BP-NOS in studies to further evaluate the clinical presentation of BP spectrum in youth and maximize the generalizability of the results.

In summary, children and adolescents with BP spectrum disorders, particularly those with early onset, BP-NOS, long duration, low SES, and psychosis, experienced frequent changes in symptom status and polarity in a fluctuating course showing a dimensional continuum of BP symptom severity, from subsyndromal to mood syndromes meeting full DSM-IV criteria. The enduring and rapid changeability of symptoms of this illness in children and adolescents from very early in life and at crucial stages of their lives deprives them of the opportunity for normal emotional, cognitive, and social development.110,58 Thus, early recognition and acute and maintenance treatment of BP spectrum disorders in children and adolescents is of utmost importance to ameliorate ongoing syndromal and subsyndromal symptoms and to reduce or prevent the serious psychosocial morbidity that usually accompanies this illness.58,59

Correspondence: Boris Birmaher, MD, Western Psychiatric Institute and Clinic, 3811 O’Hara St, Pittsburgh, PA 15213 (birmaherb@upmc.edu).

Submitted for Publication: March 16, 2005; final revision received July 7, 2005; accepted July 28, 2005.

Financial Disclosure: Dr Keller is a consultant to or has received honoraria from Bristol-Myers Squibb, Collegium Pharmaceutical, Cyberonics, Inc, Cypress Bioscience, Inc, Eli Lilly and Company, Forest Laboratories, Janssen, Merck & Co, Inc, Organon, Otsuka Pharmaceutical Co, Ltd, Pfizer, Inc, Pharmacia, PharmaStar, Sepracor Inc, Vela Pharmaceuticals Inc, and Wyeth; has received grant or research support from Eli Lilly and Company, Forest Laboratories, Merck & Co, Inc, Organon, Pfizer, Inc, and Wyeth; and is on the advisory board of Abbott Laboratories, Bristol-Myers Squibb, Cephalon, Inc, Cyberonics, Inc, Cypress Bioscience, Inc, Eli Lilly and Company, Forest Laboratories, GlaxoSmithKline, Janssen, Merck & Co, Inc, Mitsubishi Pharma Corporation, Novartis, Organon, Pfizer, Inc, Pharmacia, Sanofi-Synthelabo, SCIREX, Sepracor Inc, Somerset Pharmaceuticals, Inc, Vela Pharmaceuticals Inc, and Wyeth.

Funding/Support: This study was supported by grants MH59929 (Dr Birmaher), MH59977 (Dr Strober), and MH59691 (Dr Keller) from the National Institute of Mental Health, Rockville, Md.

Acknowledgment: We thank Carol Kostek for her assistance with manuscript preparation; Kristin Bruning, MD, and Jennifer Dyl, PhD, of the Course and Outcome of Bipolar Illness in Youth faculty; raters Mathew Arruda, BA, Mark Celio, BA, Jennifer Fretwell, BA, Michael Henry, BS, Risha Henry, PhD, Norman Kim, PhD, Marguerite Lee, BA, Marilyn Matzko, EdD, Heather Schwickrath, MA, Anna Van Meter, BA, and Matthew Young, BA; data personnel Amy Broz, AS, Colleen Grimm, BA, and Nicole Ryan, BA; and Editha Nottelmann, PhD, and Regina James, MD, for their continued support.

Biederman  JFaraone  SVWozniak  JMick  EKwon  AAleardi  M Further evidence of unique developmental phenotypic correlates of pediatric bipolar disorder: findings from a large sample of clinically referred preadolescent children assessed over the last 7 years. J Affect Disord 2004;82 ((suppl 1)) S45- S58
PubMed Link to Article
Weller  RAWeller  EBTucker  SGFristad  MA Mania in prepubertal children: has it been underdiagnosed? J Affect Disord 1986;11151- 154
PubMed Link to Article
Brent  DAPerper  JAMoritz  GAllman  CFriend  ARoth  CSchweers  JBalach  LBaugher  M Psychiatric risk factors for adolescent suicide: a case-control study. J Am Acad Child Adolesc Psychiatry 1993;32521- 529
PubMed Link to Article
Carlson  GDavenport  YJamison  K A comparison of outcome in adolescent- and late-onset bipolar manic-depressive illness. Am J Psychiatry 1977;134919- 922
PubMed
Carlson  GABromet  EJDriessens  CMojtabai  RSchwartz  JE Age at onset, childhood psychopathology, and 2-year outcome in psychotic bipolar disorder. Am J Psychiatry 2002;159307- 309
PubMed Link to Article
Findling  RLGracious  BLMcNamara  NKYoungstrom  EADemeter  CACalabrese  JR Rapid, continuous cycling and psychiatric co-morbidity in pediatric bipolar I disorder. Bipolar Disord 2001;3202- 210
PubMed Link to Article
Geller  BBolhofner  KCraney  JWilliams  MDelBello  MGundersen  K Psychosocial functioning in a prepubertal and early adolescent bipolar disorder phenotype. J Am Acad Child Adolesc Psychiatry 2000;391543- 1548
PubMed Link to Article
Geller  BTillman  RCraney  JBolhofner  K Four-year prospective outcome and natural history of mania in children with a prepubertal and early adolescent bipolar disorder phenotype. Arch Gen Psychiatry 2004;61459- 467
PubMed Link to Article
Lewinsohn  PKlein  DSeeley  J Bipolar disorders in a community sample of older adolescents: prevalence, phenomenology, comorbidity, and course. J Am Acad Child Adolesc Psychiatry 1995;34454- 463
PubMed Link to Article
Lewinsohn  PMKlein  DNSeeley  JR Bipolar disorder during adolescence and young adulthood in a community sample. Bipolar Disord 2000;2281- 293
PubMed Link to Article
Strober  MFreeman  RBower  SLampert  CDeAntonio  M Recovery and relapse in adolescents with bipolar affective illness: a five-year naturalistic, prospective follow-up. J Am Acad Child Adolesc Psychiatry 1995;34724- 731
PubMed Link to Article
Jairam  RSrinath  SGirimaji  SCSeshadri  SP A prospective 4-5 year follow-up of juvenile onset bipolar disorder. Bipolar Disord 2004;6386- 394
PubMed Link to Article
Rajeev  JSrinath  SReddy  YCShashikiran  MGGirimaji  SCSeshadri  SPSubbakrishna  DK The index manic episode in juvenile-onset bipolar disorder: the pattern of recovery. Can J Psychiatry 2003;4852- 55
PubMed
Srinath  SJanarolha  NReddy  YCGirimani  SRSeshadri  SRSubbakrishna  DK A prospective study of bipolar disorder in children and adolescents from India. Acta Psychiatr Scand 1998;98437- 442
PubMed Link to Article
Bashir  MRussell  JJohnson  G Bipolar affective disorder in adolescence: a 10-year study. Aust N Z J Psychiatry 1987;2136- 43
PubMed
Jarbin  HOtt  YVon Knorring  AL Adult outcome of social function in adolescent-onset schizophrenia and affective psychosis. J Am Acad Child Adolesc Psychiatry 2003;42176- 183
PubMed Link to Article
Welner  AWelner  ZFishman  R Psychiatric adolescent inpatients: eight- to ten-year follow-up. Arch Gen Psychiatry 1979;36698- 700
PubMed Link to Article
Landolt  AB Follow-up studies on circular manic-depressive reactions occurring in the young. Bull N Y Acad Med 1957;3365- 73
PubMed
McGlashan  TH Adolescent versus adult onset of mania. Am J Psychiatry 1988;145221- 223
PubMed
Werry  JSMcClellan  JM Predicting outcome in child and adolescent (early onset) schizophrenia and bipolar disorder. J Am Acad Child Adolesc Psychiatry 1992;31147- 150
PubMed Link to Article
Strober  MBirmaher  BRyan  NAxelson  DValeri  SLeonard  HIyengar  SGill  MKHunt  JKeller  M Pediatric bipolar disease: current and future perspectives for study of its long-term course and treatment. Bipolar Disord In press
 National Institute of Mental Health research roundtable on prepubertal bipolar disorder. J Am Acad Child Adolesc Psychiatry 2001;40871- 878
PubMed Link to Article
American Psychiatric Association, Diagnostic and Statistical Manual of Mental Disorders: Fourth Edition.  Washington DC American Psychiatric Association1994;
Kaufman  JBirmaher  BBrent  DRao  UFlynn  CMoreci  PWilliamson  DRyan  N Schedule for Affective Disorders and Schizophrenia for School-Age Children–Present and Lifetime Version (K-SADS-PL): initial reliability and validity data. J Am Acad Child Adolesc Psychiatry 1997;36980- 988
PubMed Link to Article
Axelson  DBirmaher  BBrent  DWassick  SHoover  CBridge  JRyan  N A preliminary study of the KSADS mania rating scale for children and adolescents. J Child Adolesc Psychopharmacol 2003;13463- 470
PubMed Link to Article
Chambers  WJPuig-Antich  JHirsch  MPaez  PAmbrosini  PJTabrizi  MADavies  M The assessment of affective disorders in children and adolescents by semi-structured interview test-retest reliability. Arch Gen Psychiatry 1985;42696- 702
PubMed Link to Article
Keller  MLavori  PFriedman  BNielsen  EEndicott  JMcDonald-Scott  PAndreasen  NC The longitudinal interval follow-up evaluation: a comprehensive method for assessing outcome in prospective longitudinal studies. Arch Gen Psychiatry 1987;44540- 548
PubMed Link to Article
Judd  LLAkiskal  HSSchettler  PJEndicott  J The long-term natural history of the weekly symptomatic status of bipolar I disorder. Arch Gen Psychiatry 2002;59530- 537
PubMed Link to Article
Judd  LLAkiskal  HSSchettler  PJCoryell  WEndicott  JMaser  JDSolomon  DALeon  ACKeller  MB A prospective investigation of the natural history of the long-term weekly symptomatic status of bipolar II disorder. Arch Gen Psychiatry 2003;60261- 269
PubMed Link to Article
Weissman  MMWickramaratne  PAdams  PWolk  SVerdeli  HOlfson  M Brief screening for family psychiatric history: the Family History Screen. Arch Gen Psychiatry 2000;57675- 682
Link to Article
Petersen  ACrockett  LRichards  MBoxer  A A self-report measure of pubertal status: reliability, validity, and initial norms. J Youth Adolesc 1988;17117- 133
Link to Article
Marshall  WATanner  JM Variations in pattern of pubertal changes in girls. Arch Dis Child 1969;44291- 295
PubMed Link to Article
Marshall  WATanner  JM Variations in pattern of pubertal changes in boys. Arch Dis Child 1970;4513- 23
PubMed Link to Article
Hollingshead  AB Four-Factor Index of Social Status.  New Haven, Conn Department of Sociology, Yale University1975;
Frank  EPrien  RFJarrett  RBKeller  MBKupfer  DJLavori  PWRush  AJWeissman  MM Conceptualization and rationale for consensus definitions of terms in major depressive disorder: remission, recovery, relapse, and recurrence. Arch Gen Psychiatry 1991;48851- 855
PubMed Link to Article
Birmaher  BBrent  DAKolko  DBaugher  MBridge  JHolder  DIyengar  SUlloa  RE Clinical outcome after short-term psychotherapy for adolescents with major depressive disorder. Arch Gen Psychiatry 2000;5729- 36
PubMed Link to Article
Kaplan  ELMeier  P Nonparametric estimation from incomplete observations. J Am Stat Assoc 1958;53457- 481
Link to Article
Cox  DR Regression models and life tables. J R Stat Soc [Ser A] 1972;B34187- 220
Kraepelin  E Manic Depressive Insanity and Paranoia.  Edinburgh, Scotland E & S Livingstone1921;
Perlis  RHMiyahara  SMarangell  LBWisniewski  SROstacher  MDelBello  MPBowden  CLSachs  GSNierenberg  AA Long-term implications of early onset in bipolar disorder: data from the first 1000 participants in the systematic treatment enhancement program for bipolar disorder (SEP-BD). Biol Psychiatry 2004;55875- 881
PubMed Link to Article
Turvey  CCoryell  WAmdt  SSolomon  D Polarity sequence, depression, and chronicity in bipolar I disorder. J Nerv Ment Dis 1999;187181- 187
PubMed Link to Article
Turvey  CLCoryell  WHSolomon  DALeon  ACEndicott  JKeller  MBAkiskal  H Long-term prognosis of bipolar I disorder. Acta Psychiatr Scand 1999;99110- 119
PubMed Link to Article
Keitner  GISolomon  DARyan  CEMiller  IWMallinger  AKupfer  DJFrank  E Prodromal and residual symptoms in bipolar I disorder. Compr Psychiatry 1996;37362- 367
PubMed Link to Article
Keller  MLavori  PKane  JGelenberg  ARosenbaum  JFWalzer  EBaker  M Subsyndromal symptoms in bipolar illness: a comparison of standard and low serum levels of lithium. Arch Gen Psychiatry 1992;49371- 376
PubMed Link to Article
Angst  JGerber-Werder  RZuberbühler  HUGamma  A Is bipolar I disorder heterogeneous? Eur Arch Psychiatry Clin Neurosci 2004;25482- 91
PubMed Link to Article
Coryell  WTurvey  CEndicott  JLeon  A Bipolar I affective disorder: predictors of outcome after 15 years. J Affect Disord 1998;50109- 116
PubMed Link to Article
Goodwin  FJamison  K Manic Depressive Illness.  New York, NY Oxford University Press Inc1990;
Akiskal  HSBourgeois  MLAngst  JPost  RMoller  HHirschfeld  R Re-evaluating the prevalence of and diagnostic composition within the broad clinical spectrum of bipolar disorders. J Affect Disord 2000;59 ((suppl 1)) S5- S30
PubMed Link to Article
Post  RMDenicoff  KDLeverich  GSAltshuler  LLFrye  MASuppes  TMRush  AJKeck  PE  JrMcElroy  SLLuckenbaugh  DAPollio  CKupka  RNolen  WA Morbidity in 258 bipolar outpatients followed for 1 year with daily prospective ratings on the NIMH life chart method. J Clin Psychiatry 2003;64680- 690
PubMed Link to Article
Schneck  CDMiklowitz  DJCalabrese  JRAllen  MHThomas  MRWisniewski  SRMiyahara  SShelton  MDKetter  TAGoldberg  JFBowden  CLSachs  GS Phenomenology of rapid-cycling bipolar disorder: data from the first 500 participants in the systematic treatment enhancement program. Am J Psychiatry 2004;1611902- 1908
PubMed Link to Article
Coryell  WSolomon  DTurvey  CKeller  MLeon  ACEndicott  JSchettler  PJudd  LMueller  T The long-term course of rapid-cycling bipolar disorder. Arch Gen Psychiatry 2003;60914- 920
PubMed Link to Article
Tohen  MHennen  JZarate  CM  JrBaldessarini  RJ  et al.  Two-year syndromal and functional recovery in 219 cases of first-episode major affective disorder with psychotic features. Am J Psychiatry 2000;157220- 228
PubMed Link to Article
Tohen  MZarate  CA  JrHennen  JKhalsa  HStrakowski  SMGebre-Medhin  PSalvatore  PBaldessarini  RJ The McLean-Harvard First-Episode Mania Study: prediction of recovery and first recurrence. Am J Psychiatry 2003;1602099- 2107
PubMed Link to Article
Coryell  WEndicott  JMaser  JDKeller  MBLeon  ACAkiskal  HS Long-term stability of polarity distinctions in the affective disorders. Am J Psychiatry 1995;152385- 390
PubMed
Hazell  PLCarr  VLewin  TJSly  K Manic symptoms in young males with ADHD predict functioning but not diagnosis after 6 years. J Am Acad Child Adolesc Psychiatry 2003;42552- 560
PubMed Link to Article
Nolen  WALuckenbaugh  DAAltshuler  LLSuppes  TMcElroy  SLFrye  MAKupka  RWKeck  PELeverich  GSPost  RM Correlates of 1-year prospective outcome in bipolar disorder: results from the Stanley Foundation Bipolar Network. Am J Psychiatry 2004;1611447- 1454
PubMed Link to Article
Leibenluft  ECharney  DSTowbin  KEBhangoo  RKPine  DS Defining clinical phenotypes of juvenile mania. Am J Psychiatry 2003;160430- 437
PubMed Link to Article
Pavuluri  MNBirmaher  BNaylor  MW Pediatric bipolar disorder: a review of the past 10 years. J Am Acad Child Adolesc Psychiatry 2005;44846- 871
PubMed Link to Article
Kowatch  RAFristad  MABirmaher  BWagner  KDFindling  RLHellander  MChild Psychiatric Workgroup Members, Treatment guidelines for children and adolescents with bipolar disorder: Child Psychiatric Workgroup on Bipolar Disorder. J Am Acad Child Adolesc Psychiatry 2005;44213- 235
PubMed Link to Article

Figures

Place holder to copy figure label and caption
Figure 1.

Recovery stratified by bipolar subtype. The index episode was defined as the most recent or current episode from the date 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 exceeded the length of prospective follow-up. BP-I indicates bipolar I disorder; BP-II, bipolar II disorder; BP-NOS, bipolar disorder not otherwise specified.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 2.

Recurrence stratified by bipolar subtype. Time to recurrence was calculated from the time subjects fulfilled criteria for recovery until they met full criteria for a new mood episode. Abbreviations are explained in the legend to Figure 1.

Graphic Jump Location

Tables

Table Graphic Jump LocationTable 1. Demographic and Clinical Characteristics Among Subjects With BP-I, BP-II, and BP-NOS*
Table Graphic Jump LocationTable 2. Summary of Recovery and Recurrence by BP Subtype*
Table Graphic Jump LocationTable 3. Weekly Symptomatic Status by Bipolar Subtype*
Table Graphic Jump LocationTable 4. Comparison of Weekly Symptom Status, Change in Symptom Status and Polarity, and Time With Psychosis Between Youth and Adults With BP-I*

References

Biederman  JFaraone  SVWozniak  JMick  EKwon  AAleardi  M Further evidence of unique developmental phenotypic correlates of pediatric bipolar disorder: findings from a large sample of clinically referred preadolescent children assessed over the last 7 years. J Affect Disord 2004;82 ((suppl 1)) S45- S58
PubMed Link to Article
Weller  RAWeller  EBTucker  SGFristad  MA Mania in prepubertal children: has it been underdiagnosed? J Affect Disord 1986;11151- 154
PubMed Link to Article
Brent  DAPerper  JAMoritz  GAllman  CFriend  ARoth  CSchweers  JBalach  LBaugher  M Psychiatric risk factors for adolescent suicide: a case-control study. J Am Acad Child Adolesc Psychiatry 1993;32521- 529
PubMed Link to Article
Carlson  GDavenport  YJamison  K A comparison of outcome in adolescent- and late-onset bipolar manic-depressive illness. Am J Psychiatry 1977;134919- 922
PubMed
Carlson  GABromet  EJDriessens  CMojtabai  RSchwartz  JE Age at onset, childhood psychopathology, and 2-year outcome in psychotic bipolar disorder. Am J Psychiatry 2002;159307- 309
PubMed Link to Article
Findling  RLGracious  BLMcNamara  NKYoungstrom  EADemeter  CACalabrese  JR Rapid, continuous cycling and psychiatric co-morbidity in pediatric bipolar I disorder. Bipolar Disord 2001;3202- 210
PubMed Link to Article
Geller  BBolhofner  KCraney  JWilliams  MDelBello  MGundersen  K Psychosocial functioning in a prepubertal and early adolescent bipolar disorder phenotype. J Am Acad Child Adolesc Psychiatry 2000;391543- 1548
PubMed Link to Article
Geller  BTillman  RCraney  JBolhofner  K Four-year prospective outcome and natural history of mania in children with a prepubertal and early adolescent bipolar disorder phenotype. Arch Gen Psychiatry 2004;61459- 467
PubMed Link to Article
Lewinsohn  PKlein  DSeeley  J Bipolar disorders in a community sample of older adolescents: prevalence, phenomenology, comorbidity, and course. J Am Acad Child Adolesc Psychiatry 1995;34454- 463
PubMed Link to Article
Lewinsohn  PMKlein  DNSeeley  JR Bipolar disorder during adolescence and young adulthood in a community sample. Bipolar Disord 2000;2281- 293
PubMed Link to Article
Strober  MFreeman  RBower  SLampert  CDeAntonio  M Recovery and relapse in adolescents with bipolar affective illness: a five-year naturalistic, prospective follow-up. J Am Acad Child Adolesc Psychiatry 1995;34724- 731
PubMed Link to Article
Jairam  RSrinath  SGirimaji  SCSeshadri  SP A prospective 4-5 year follow-up of juvenile onset bipolar disorder. Bipolar Disord 2004;6386- 394
PubMed Link to Article
Rajeev  JSrinath  SReddy  YCShashikiran  MGGirimaji  SCSeshadri  SPSubbakrishna  DK The index manic episode in juvenile-onset bipolar disorder: the pattern of recovery. Can J Psychiatry 2003;4852- 55
PubMed
Srinath  SJanarolha  NReddy  YCGirimani  SRSeshadri  SRSubbakrishna  DK A prospective study of bipolar disorder in children and adolescents from India. Acta Psychiatr Scand 1998;98437- 442
PubMed Link to Article
Bashir  MRussell  JJohnson  G Bipolar affective disorder in adolescence: a 10-year study. Aust N Z J Psychiatry 1987;2136- 43
PubMed
Jarbin  HOtt  YVon Knorring  AL Adult outcome of social function in adolescent-onset schizophrenia and affective psychosis. J Am Acad Child Adolesc Psychiatry 2003;42176- 183
PubMed Link to Article
Welner  AWelner  ZFishman  R Psychiatric adolescent inpatients: eight- to ten-year follow-up. Arch Gen Psychiatry 1979;36698- 700
PubMed Link to Article
Landolt  AB Follow-up studies on circular manic-depressive reactions occurring in the young. Bull N Y Acad Med 1957;3365- 73
PubMed
McGlashan  TH Adolescent versus adult onset of mania. Am J Psychiatry 1988;145221- 223
PubMed
Werry  JSMcClellan  JM Predicting outcome in child and adolescent (early onset) schizophrenia and bipolar disorder. J Am Acad Child Adolesc Psychiatry 1992;31147- 150
PubMed Link to Article
Strober  MBirmaher  BRyan  NAxelson  DValeri  SLeonard  HIyengar  SGill  MKHunt  JKeller  M Pediatric bipolar disease: current and future perspectives for study of its long-term course and treatment. Bipolar Disord In press
 National Institute of Mental Health research roundtable on prepubertal bipolar disorder. J Am Acad Child Adolesc Psychiatry 2001;40871- 878
PubMed Link to Article
American Psychiatric Association, Diagnostic and Statistical Manual of Mental Disorders: Fourth Edition.  Washington DC American Psychiatric Association1994;
Kaufman  JBirmaher  BBrent  DRao  UFlynn  CMoreci  PWilliamson  DRyan  N Schedule for Affective Disorders and Schizophrenia for School-Age Children–Present and Lifetime Version (K-SADS-PL): initial reliability and validity data. J Am Acad Child Adolesc Psychiatry 1997;36980- 988
PubMed Link to Article
Axelson  DBirmaher  BBrent  DWassick  SHoover  CBridge  JRyan  N A preliminary study of the KSADS mania rating scale for children and adolescents. J Child Adolesc Psychopharmacol 2003;13463- 470
PubMed Link to Article
Chambers  WJPuig-Antich  JHirsch  MPaez  PAmbrosini  PJTabrizi  MADavies  M The assessment of affective disorders in children and adolescents by semi-structured interview test-retest reliability. Arch Gen Psychiatry 1985;42696- 702
PubMed Link to Article
Keller  MLavori  PFriedman  BNielsen  EEndicott  JMcDonald-Scott  PAndreasen  NC The longitudinal interval follow-up evaluation: a comprehensive method for assessing outcome in prospective longitudinal studies. Arch Gen Psychiatry 1987;44540- 548
PubMed Link to Article
Judd  LLAkiskal  HSSchettler  PJEndicott  J The long-term natural history of the weekly symptomatic status of bipolar I disorder. Arch Gen Psychiatry 2002;59530- 537
PubMed Link to Article
Judd  LLAkiskal  HSSchettler  PJCoryell  WEndicott  JMaser  JDSolomon  DALeon  ACKeller  MB A prospective investigation of the natural history of the long-term weekly symptomatic status of bipolar II disorder. Arch Gen Psychiatry 2003;60261- 269
PubMed Link to Article
Weissman  MMWickramaratne  PAdams  PWolk  SVerdeli  HOlfson  M Brief screening for family psychiatric history: the Family History Screen. Arch Gen Psychiatry 2000;57675- 682
Link to Article
Petersen  ACrockett  LRichards  MBoxer  A A self-report measure of pubertal status: reliability, validity, and initial norms. J Youth Adolesc 1988;17117- 133
Link to Article
Marshall  WATanner  JM Variations in pattern of pubertal changes in girls. Arch Dis Child 1969;44291- 295
PubMed Link to Article
Marshall  WATanner  JM Variations in pattern of pubertal changes in boys. Arch Dis Child 1970;4513- 23
PubMed Link to Article
Hollingshead  AB Four-Factor Index of Social Status.  New Haven, Conn Department of Sociology, Yale University1975;
Frank  EPrien  RFJarrett  RBKeller  MBKupfer  DJLavori  PWRush  AJWeissman  MM Conceptualization and rationale for consensus definitions of terms in major depressive disorder: remission, recovery, relapse, and recurrence. Arch Gen Psychiatry 1991;48851- 855
PubMed Link to Article
Birmaher  BBrent  DAKolko  DBaugher  MBridge  JHolder  DIyengar  SUlloa  RE Clinical outcome after short-term psychotherapy for adolescents with major depressive disorder. Arch Gen Psychiatry 2000;5729- 36
PubMed Link to Article
Kaplan  ELMeier  P Nonparametric estimation from incomplete observations. J Am Stat Assoc 1958;53457- 481
Link to Article
Cox  DR Regression models and life tables. J R Stat Soc [Ser A] 1972;B34187- 220
Kraepelin  E Manic Depressive Insanity and Paranoia.  Edinburgh, Scotland E & S Livingstone1921;
Perlis  RHMiyahara  SMarangell  LBWisniewski  SROstacher  MDelBello  MPBowden  CLSachs  GSNierenberg  AA Long-term implications of early onset in bipolar disorder: data from the first 1000 participants in the systematic treatment enhancement program for bipolar disorder (SEP-BD). Biol Psychiatry 2004;55875- 881
PubMed Link to Article
Turvey  CCoryell  WAmdt  SSolomon  D Polarity sequence, depression, and chronicity in bipolar I disorder. J Nerv Ment Dis 1999;187181- 187
PubMed Link to Article
Turvey  CLCoryell  WHSolomon  DALeon  ACEndicott  JKeller  MBAkiskal  H Long-term prognosis of bipolar I disorder. Acta Psychiatr Scand 1999;99110- 119
PubMed Link to Article
Keitner  GISolomon  DARyan  CEMiller  IWMallinger  AKupfer  DJFrank  E Prodromal and residual symptoms in bipolar I disorder. Compr Psychiatry 1996;37362- 367
PubMed Link to Article
Keller  MLavori  PKane  JGelenberg  ARosenbaum  JFWalzer  EBaker  M Subsyndromal symptoms in bipolar illness: a comparison of standard and low serum levels of lithium. Arch Gen Psychiatry 1992;49371- 376
PubMed Link to Article
Angst  JGerber-Werder  RZuberbühler  HUGamma  A Is bipolar I disorder heterogeneous? Eur Arch Psychiatry Clin Neurosci 2004;25482- 91
PubMed Link to Article
Coryell  WTurvey  CEndicott  JLeon  A Bipolar I affective disorder: predictors of outcome after 15 years. J Affect Disord 1998;50109- 116
PubMed Link to Article
Goodwin  FJamison  K Manic Depressive Illness.  New York, NY Oxford University Press Inc1990;
Akiskal  HSBourgeois  MLAngst  JPost  RMoller  HHirschfeld  R Re-evaluating the prevalence of and diagnostic composition within the broad clinical spectrum of bipolar disorders. J Affect Disord 2000;59 ((suppl 1)) S5- S30
PubMed Link to Article
Post  RMDenicoff  KDLeverich  GSAltshuler  LLFrye  MASuppes  TMRush  AJKeck  PE  JrMcElroy  SLLuckenbaugh  DAPollio  CKupka  RNolen  WA Morbidity in 258 bipolar outpatients followed for 1 year with daily prospective ratings on the NIMH life chart method. J Clin Psychiatry 2003;64680- 690
PubMed Link to Article
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