Corroborating prior COBY findings,4
this study showed that bipolar spectrum disorders in youth are episodic disorders most often characterized by subsyndromal episodes and, less frequently, by syndromal episodes, with mainly depressive and mixed symptoms and rapid mood changes.
Utilizing the standard DSM-IV and literature definitions of syndromal recovery and recurrence, survival analyses indicated that about 2.5 years after onset of their index episode approximately 80% of youth with bipolar spectrum disorder achieved full recovery. However, 1.5 years after full recovery, approximately 60% of the subjects had at least one syndromal recurrence. Compared to youth with bipolar-NOS, youth with bipolar-I and II were more likely to recover but have less durable recovery.
During the entire follow-up period, 1/3 of the subjects had at least one syndromal recurrence and 30% experienced ≥ 2 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 polarity of subsequent episodes.
The above analyses only focused on recovery and recurrence of syndromal symptoms. Complementary 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 youth with bipolar spectrum disorder. However, they are embedded in more prevailing and longer periods of subsyndromal mood symptomatology. More specifically, youth with bipolar spectrum disorders were symptomatic during 60% of the follow-up time, during which subjects spent about 2.5 times more time with subsyndromal than syndromal symptomatology. Mixed/cycling and depressive symptoms accounted for the greatest proportion of time ill. In contrast, purely manic symptomatology, especially at the full syndromic level, was less common. Rapid mood changes were ubiquitous and psychotic symptoms were relatively common, particularly in subjects with bipolar-I. Chronic symptoms, defined as 75% or more of the follow-up time with any type of symptoms, were present in 38% of the subjects. Almost all of these chronic symptoms were subsyndromal and of the depressive type.
The week-by-week analyses also shed light on the similarities and differences in the longitudinal patterns of symptom phenomenology of youth with bipolar-I, II and NOS. Bipolar-I was manifested with more time with subsyndromal than syndromal symptoms. Most of the syndromal time was characterized by mixed/cycling or depressive symptoms and most of the subsyndromal time was with subsyndromal manic or mixed symptoms. Youth with bipolar-II spent equal amounts of time in syndromal and subsyndromal states. The syndromal episodes were most commonly depression or mixed states, but there were no differences in the time spent with any type of subsyndromal symptoms. Finally, bipolar-NOS was mainly manifested by periods of subsyndromal mixed symptoms, closely followed by periods of subsyndromal manic or depressive symptoms.
Between-group comparisons provided preliminary validation for the subtyping of bipolar disorder in youth. In general, in comparison with other subtypes, each bipolar subtype continued to show some category specific symptomatology. For example, during follow-up, youth whose initial diagnosis was bipolar-I showed more syndromal, mixed/rapid cycling and manic/hypomanic symptoms than those with bipolar-NOS; youth with bipolar-II spent more time in hypomania than those with bipolar-NOS and more time in depression than those with bipolar-I and NOS; and youth with bipolar-NOS spent significantly more follow-up time with subsyndromal symptoms than did subjects with bipolar-I and II. However, there was some symptom overlap among the different bipolar subtypes, especially in those with BP-I and II. Moreover, 25% of bipolar-II subjects converted into bipolar-I and 38% of bipolar-NOS converted into bipolar-I and II.
Although there were some differences in the demographic and clinical factors associated with the outcome variables measured (e.g., recovery, time symptomatic, and changes in polarity), in general, early-onset of bipolar disorder, presence of comorbid disorders, family history of mood disorders (particularly mania/hypomania), low socio-economic status, and non-Caucasian race were associated with worse outcome. Long duration of illness was also associated with less 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, despite the efforts to obtain precise information, the data collected through the Longitudinal Interval Following Evaluation is subject to retrospective recall bias. Although it appears that this instrument has adequate psychometric properties,1, 4, 11
further studies using the methods described by Warsaw et al., 11
and including blind interviewers are warranted. Second, although COBY utilized the standard literature definitions of course for recovery and recurrence, 1, 3, 17
the rates and length of the mood episodes may change according to the duration criteria and symptom threshold severity chosen. Third, the results pertaining to subjects with bipolar-II should be considered tentative given the relatively small size of this group. However, across all bipolar subtypes, after depression most syndromal recurrences were hypomanias. Finally, as most subjects were Caucasian and were recruited primarily from outpatient, and to a lesser extent, from inpatient settings, the generalizability of the observations to other populations remains uncertain. Nevertheless, non-referred adolescents with bipolar disorder have been shown to have similar course and high morbidity. 5
Despite methodological differences, all existing studies of the course of bipolar disorder in youth, regardless of country and source of ascertainment, show that likelihood of recovery from the index episode is high. 1–4
However, as with adult populations, in spite of the high rate of recovery, the rates of recurrence, persistence of subsyndromal clinical morbidity, and rapid and frequent changes in mood polarity is also high and most syndromal and subsyndromal recurrences are depressions.15, 18–22
However, it appears that the polarity of the index episode predicts polarity of the subsequent episodes, 20, 23–27
and 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 youth and adults with the longitudinal course mainly manifested by subsyndromal symptomatology and rapid mood changes. 1–4, 28
However, there is evidence that very early-onset appears to confer greater liability for a more chronic and fluctuating course, mixed/cycling episodes, high rates of comorbid disorders, and increased rates of mood disorders in families.1, 3, 29–31
Converging with these accounts are reports indicating that adults whose onset of bipolar is dated to childhood have a more severe and chronic course, more episodes, changes in mood polarity, suicidality, and comorbidity, and lower quality of life. 32–34
Comparable with other literature, childhood-onset bipolar disorder, comorbid disorders, positive family history for mood disorders, and low socio-economic status were associated with poorer outcome.1–4, 6
Moreover, there was decreasing probability of recovery with increasing duration of illness. This further underscores the importance of early detection of illness and rapid implementation of stabilizing treatments, which may be of even greater urgency for youth with bipolar disorder and with risk factors associated with poorer outcome.
Similar to literature on major depression, 35
it appears that there are some differences in the factors associated with the various indices of clinical outcome (e.g., recovery, recurrence, time symptomatic). 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. As an example, since youth with depression were seen to have more depressive recurrences, they may require more aggressive and specific therapies to reduce the risk of future depressive episodes.
To our knowledge, and of importance given the modal age of onset of bipolar-II illness during adolescence, 17, 26, 36
COBY is the first naturalistic, prospective study of this affective subtype in youth. Consistent with adult data on high levels of morbidity associated with this subtype, bipolar-II had greater overall recurrence risk and more depressive morbidity compared to youth with bipolar-I, and had comparable rates of non-affective comorbidity, suicidality, non-suicidal self-injurious behaviors, functional impairment, and family history for mood and bipolar disorders as youth with bipolar-I.6, 7, 31, 37–39
Also, bipolar-II in youth appears to be a far less stable phenotype than in adults as 25% of the bipolar-II youth in this cohort converted to bipolar-I, a rate higher than that reported in adult studies.40
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 erratic behavior, and perhaps more so in adolescents,26, 41
such that the risk of misclassification as recurrent unipolar depression or other non-affective disorders is high.
Bipolar-NOS was characterized by rates of comorbidity, suicidality, functional impairment (except hospitalizations), and family history for mood disorders equivalent to those in subjects with bipolar-I and II.6, 7, 31, 37–39
These findings together with the high rates of conversion to bipolar-I or II, provide preliminary validation of its nosological affinity with bipolar disorder. It is to be stressed, however, that our classification relied on the presence of an affective phenotype that differed from bipolar-I or II due to failure to meet DSM-IV duration requirements for these subtypes. Thus, our findings are in concert with adult literature 17, 41, 42
emphasizing the clinical relevance of this phenomenon, yet one that is often overlooked given the predominance of syndromal depression and subsyndromal manic/mixed symptoms of short duration in its expression. Results from COBY suggest that bipolar-NOS is an episodic
illness, albeit often comprising subsyndromic episodes that should be considered different from youth with behavior disorders and “severe mood dysregulation”.43
In summary, although distinct episodes of full syndromic mood symptomatology as well as durable periods of euthymia can be identified in youth with bipolar disorder, the course of bipolar spectrum disorders among children and adolescents is predominantly characterized by subsyndromal and, much less frequently, syndromal episodes. Rapid mood changes are evident during these episodes, which are mainly of depressive and mixed polarity. At follow-up each bipolar subtype showed some distinct clinical characteristics and course, but there was overlap in their symptoms and substantial conversion from bipolar II and NOS into other bipolar subtypes. The course of bipolar disorder, the relative infrequency of syndromic DSM manic episodes, the effects of development in symptom manifestation and the high prevalence of comorbid disorders may account, at least in part, for the difficulties in recognizing and managing this illness in youth. The recurrence, chronicity, and psychosocial morbidity associated with this illness in critical developmental stages calls for its prompt recognition and the development of more efficacious treatments, particularly since each year of illness appears to decrease the likelihood of recovery.