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.9,10,27–29
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,5–15
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,8–14
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.28,29,39–49
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 (). 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.
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
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.1–10,58
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