This study found that 45% of youth with distinct, but subthreshold episodes of manic symptoms meeting COBY BP-NOS criteria, progressed to BP type I or type II illness during an average of 5 years of prospective follow-up. Morbidity from manic symptomatology following onset of the transition from subthreshold to full syndromic illness was significant, as these subjects spent a median of 4.5% of weeks in a Manic, Mixed, or Hypomanic Episode, and 71% of converters met episode criteria for two or more weeks post-conversion. The only individual clinical factor assessed at intake that predicted diagnostic conversion in the univariate analysis was a Family History of Mania or Hypomania; specifically after 5 years of follow-up, 58% of BP-NOS subjects with a positive family history of BP converted to BP-I or II as compared to 36% whose family history was negative. Multivariate analyses identified four additional factors, that when taken together with a family history of BP, were associated with conversion: White race, Lifetime History of Psychiatric Hospitalization, Severity of Manic Symptoms at intake (MRS score), and a Negative Lifetime History of Psychotic Symptoms. However, as the effect sizes of these additional factors were small, their significance is deemed to be limited.
With regard to the analysis of time varying covariates assessed longitudinally, we found that peak severity of hypomanic symptomatology prior to conversion was significantly associated with a higher hazard rate of conversion. Similar results were found in the sensitivity analyses that removed the 15% of COBY BP-NOS subjects who had a lifetime history of a Hypomanic Episode at intake. The one exception was that onset of a Manic, Mixed or Hypomanic Episode over follow-up was associated with a lower percentage of follow-up weeks free of significant mood symptoms prior to conversion, instead of peak severity of hypomanic symptoms. Overall, these results indicate that the BP-NOS subjects who showed progression of illness had a higher burden of mood symptoms prior to conversion than those who did not progress. That we observed a higher amount of psychosocial treatment in the converters is in accord with the clinical findings suggesting greater overall symptom morbidity
Significant manic symptomatology was present in the month leading up to a prospective follow-up assessment in most (85%) subjects. Similar to what was found at the intake assessment, multiple symptoms specific to mania were present in nearly all of these subjects and greater than 90% had Elated/Elevated Mood. Also similar to what was found at intake, the BP-NOS subjects continued to have high rates of comorbid disorders, indicating a substantial burden of non-mood psychopathology.
In many ways, these analyses are notable for the lack of association between diagnostic progression to BP-I or BP-II and a wide variety of clinical variables. Therefore, we could not identify clinical profiles that would strongly predict diagnostic conversion. Surprisingly, though 41% of COBY BP-NOS subjects had a history of a Major Depressive Episode at intake, this was not predictive of diagnostic conversion in both the primary analysis and in the sensitivity analysis. History of a Hypomanic Episode at intake also was not associated with conversion to BP-I or II. Diagnostic progression occurred regardless of exposure to antimanic treatment, whereas greater exposure to psychosocial intervention anticipated conversion. It is important to note in this regard that our analyses only examined treatment exposure to different medication classes as a dichotomous factor and did not examine dose intensity of different medications. The association with conversion and psychosocial treatment was driven entirely by a greater hazard of conversion in subjects exposed to specialized intensive non-inpatient psychosocial treatments. In regards to this seemingly paradoxical finding, we hypothesize that greater affective morbidity among subjects who eventually convert could be “driving” treatment seeking for these intensive services.
Limitations of the study are important to consider. Diagnosis at intake was based on a semi-structured interview using information obtained via the retrospective recall of the subjects and their caretakers; accuracy of recall could be an issue. Similar uncertainties apply to the longitudinal follow-up interviews, though the interval between assessments was 8 months on average. Follow-up interviewers were not blind to prior diagnoses and not explicitly blinded to the family history information collected at the intake assessment. This has the potential to introduce bias that could increase the association between diagnostic progression and family history. Diagnostic reliability was substantial, but not to the level of “near perfect”.39
In addition, the reliability assessment procedure did not measure information variance (i.e. independent interviewers may elicit different information from the same subject), which could be an unknown source of diagnostic unreliability. Two important factors (longest duration of episode and total lifetime days of manic/hypomanic symptoms) were measured retrospectively and in only a subset of subjects. The “typical” duration of manic/hypomanic periods for each subject was not assessed. Family history of 1st
degree relatives (other than the primary caregiver) was not obtained through direct interview. Given that COBY subjects were ascertained from multiple sources, the findings may not generalize to either community or different clinical settings. Lastly, since the vast majority of subjects in COBY had received treatment prior to intake and most continued to receive treatment over the follow-up, these results may not generalize to untreated samples.
Although the criteria for subthreshold BP was less stringent than COBY, the study by Nadkarni and Fristad had similar rates of conversion to BP-I or BP-II over 18 months of follow-up.15
However the rate of diagnostic progression in COBY is in strong contrast to that of the subthreshold BP subjects in the Lewinsohn et al. study.13
This may in part be due to different diagnostic thresholds, as the Lewinsohn study required only a distinct period of abnormally elated and/or irritable mood for inclusion in the subthreshold BP group. It also may be related to differences in ascertainment (referred vs. community), assessment procedures (caregiver informant included for COBY subjects vs. subject only) and/or assessment frequency (average of 8 months vs. an interval of 6 years). Family history was not assessed in the Lewinsohn study, so we cannot compare the rate of familial BP to the high rate (51%) of positive history of Bipolar Disorder in either a 1st
degree relative in the COBY sample.
Family history was a potent predictor of diagnostic conversion from MDD to BP-I or II in the Collaborative Depression Study, though the other factors associated with conversion, such as number of manic symptoms at baseline, psychosis and age of onset, were not significant in the COBY BP-NOS sample.22
In this regard, it is important to note that even with a family history of bipolarity, many COBY BP-NOS subjects did not progress to BP-I or II. However, given that the onset of BP-I/BP-II frequently occurs after 25 years of age40
and that the average follow-up duration was five years, the long-term stability of this phenotype remains to be fully determined.
The COBY BP-NOS phenotype differs from the proposed Disruptive Mood Dysregulation Disorder diagnosis for the DSM-5, whose core features are chronic irritability with recurrent severe temper outbursts, and from SMD, which includes these elements plus ADHD-like symptoms of hyperarousal.41
Though a large majority of COBY subjects with BP-NOS have chronic psychopathology in the context of comorbid non-affective disorders and subsyndromal mood disturbances, they must by definition also have distinct periods of manic or hypomanic symptomatology that represent a departure from their customary functioning. Therefore results from this study do not necessarily apply to non-episodic presentations of manic symptoms that have been labeled BP-NOS in the literature.
These findings have potential implications for diagnostic classification. That many of the COBY youth who presented clinically with “subthreshold” Bipolar Disorder progressed to full syndromal BP-I or II, raises questions about the current diagnostic criteria for BP illness. Combined with the data from the adult literature, it is possible that BP includes a phenotype of recurrent brief episodes of manic symptoms and further research into the appropriateness of the duration criteria for manic and hypomanic episodes is clearly warranted. Whether or not the typical initial presentation of pediatric BP is recurrent subthreshold episodes progressing to full syndromal disorder is an important question that cannot be answered by this study. Cyclothymia and subthreshold presentations of BP are common in the child and adolescent offspring of bipolar parents.42–45
A recent study reported that children of BP parents have a 13 times higher odds of meeting criteria for COBY-defined BP-NOS as compared to community controls.44
In addition, BP-NOS (7.2%) was much more commonly diagnosed in the offspring of BP parents than BP-I (2.1%) or BP-II (1.3%).44
Longitudinal follow-up will determine whether the rate of diagnostic progression from subthreshold BP to BP-I/II in a genetically high-risk sample is similar to that of COBY.
Clinical implications of these findings need to be considered with caution. The diagnostic criteria for COBY BP-NOS were intentionally set to be broad for research purposes. We chose to operationalize a minimum time threshold for distinct (hypo)manic symptomatology to be present for a significant part of the day in order to avoid classification of transient phenomena as BP-NOS. The four-hour (not necessarily consecutive throughout the day) minimum threshold was taken from the KSADS-P Elated Mood item. In practice, it has functioned reasonably well, as informants (many of whom did not see the child for much of the day) seemed comfortable estimating whether observable symptomatology was present for greater than or less than four hours. One could argue that most of the day would be a better threshold and based on our clinical experience, many of the COBY BP-NOS subjects with “1-day” episodes would have met this criterion. Those that did not meet the “most of the day” standard often had irritability and/or depressive features for much of the remaining time, so they had mood symptoms most of the day, just not distinctly (hypo)manic symptoms. The results of the Pittsburgh subanalysis (taken with the limitations noted above) indicate that most of the COBY subjects far exceeded the four lifetime days diagnostic threshold. Though we did not find phenomenological factors that predicted diagnostic progression, it is reasonable to suggest that clinical applications of the COBY BP-NOS criteria should use a higher threshold for lifetime days (e.g. at least 7 days) and that the 4-hour minimum threshold should be used in conjunction with the presence of other mood symptoms for most of the day. Diagnostic confidence in identifying a bipolar syndrome may increase with longer (e.g. 2 days) and more recurrent episodes and with the presence of symptoms specific to mania (elated mood, decreased need for sleep, grandiosity, etc.), but these are, at present, possibilities that require further empirical study..
Treatment guidelines for COBY BP-NOS do not exist, and one controlled treatment study of subthreshold BP youth failed to show a benefit of active medication over placebo.46
However, the fact that over half of the youth presenting clinically with COBY BP-NOS who have a family history of BP are likely to progress to BP-I/II, should be taken into consideration when weighing the risks and benefits of different treatment options. Future efforts to identify these high-risk youth and studies designed specifically to evaluate effective interventions may have the potential to reduce affective morbidity and curtail the progression of illness to full diagnostic threshold Bipolar Disorder.