As compared with offspring of control parents, offspring of parents with BP showed a 14-fold increase in the rates of BP spectrum disorders and approximately a 2- to 3-fold increase in any mood and anxiety disorders after adjusting for both biological parents' non-BP psychiatric disorders, significant between-group demographic variables, and within-family correlations. Also, the offspring of parents with BP and higher SES showed 4- and 6-fold increases in the rates of any Axis I disorders and DBDs, respectively. Families in which both parents had BP had more offspring with BP spectrum disorders than families in which only 1 parent had BP. Most of the offspring's BP episodes started during childhood, with most first episodes being of the NOS type and, to a lesser degree, depression episodes. As expected, about 85.0% of children with BP had other comorbid disorders, mainly anxiety disorders, DBDs, and ADHD.
Before discussing each of the earlier-noted findings, the limitations of the study deserve comment. First, because most children have not reached the age of highest risk to develop BP, the rate of BP in these children is likely to continue to increase with further follow-up. Second, as in any pediatric study, the probands for both the BP and control groups were much more likely to be the mothers rather than the fathers. In addition, the psychopathology in the biological coparents was mainly ascertained by interviewing the probands. However, there were no between-group differences in rates of mothers serving as the probands and no differences in the proportion of direct and indirect interviews of the co-biological parents with BP and control parents. Third, because the diagnosis of BP-II in adults appears to be low even with direct interviews,32
it is possible that in using indirect interviews we could have missed some of these diagnoses in relatives of both groups. Nevertheless, the rates of BP-II found in the study are similar to those reported in epidemiological studies.33,34
Fourth, although there are contradictory results in the literature and the effects seem to be small,35-38
parents with psychopathology could have been more interested in having their children evaluated through the study and may have had greater knowledge of the disorder, possibly inflating the rate of disorders in their offspring. However, at least for the control parents (of whom 50% had psychopathology), the rates of lifetime psychiatric disorders in their offspring were similar to those described in other community studies.39-41
Finally, although the literature is controversial,42,43
parents who participated in BIOS could have had more psychopathology than those who did not participate. However, the rates of psychiatric disorders in parents with BP and their age at BP onset were similar to those reported in the adult BP literature.1,33,34,44,45
Moreover, parents with BP and control parents with non-BP psychopathology were comparable in demographic characteristics and recruitment origin. Finally, taking into consideration the age and sex of the control parents recruited in BIOS, the lifetime prevalence of psychiatric disorders found in these parents is similar to that reported in a recent large epidemiological study in the United States.46
Both biological parents of the offspring of parents with BP showed considerably higher rates of Axis I psychiatric disorders than the control parents. Thus, it is not surprising that their offspring showed more psychopathology than the offspring of control parents. However, together with prior “top-down”5,10-16
and “bottom-up” BP family studies,1,3,47-51
BIOS provides further evidence that offspring of parents with BP are at specifically high risk to develop early-onset BP. Noticeably and similar to BIOS, in a review of the adult BP literature, the average age-adjusted lifetime prevalence for BP spectrum disorders in first-degree relatives was 10.7%, compared with 1.0% for the relatives of healthy control subjects.1
In BIOS, most of the children diagnosed with BP fulfilled the operationalized criteria for BP-NOS7,24
and 56.0% of the first episodes were of the NOS type. As in another investigation,7
most of these youth did not meet criteria for BP-I or BP-II because they lacked the current DSM-IV
episode duration requirements for the diagnosis of these disorders. Thus, it appears that early-onset BP with genetic loading may often present with subthreshold manic symptoms before reaching full DSM-IV
criteria for BP-I or BP-II. Because youth with the stricter definition of BP-NOS are at high risk for diagnoses converting to BP-I or BP-II,23
follow-up of the subjects with BP-NOS in BIOS will provide an additional test of the validity of the BP-NOS phenotype in a nonreferred high-risk sample.
Consistent with the literature,2,45,52-54
most parents with BP recollected that their illness started before age 20 years and about 20.0% had illness that started before age 13 years. In contrast, most of their children developed their first BP episode before age 12 years, suggesting the possibility that parents were more perceptive of their children's symptoms early in life or perhaps that BP has more penetrance and manifests earlier in new generations.45,52,55
Offspring of families in which both parents had BP were 3.6 times more likely to have BP, without being at higher risk for any other psychiatric disorders as compared with families with only 1 parent with BP. One child study and other adult family studies reported similar findings,1,56
giving further evidence to the specificity of the family transmission of BP. Future articles will examine the earlier-noted results in greater depth and analyze other important issues such as the parent-of-origin effect and the effects of second-degree family psychopathology.
Similar to a meta-analysis of studies of pediatric high risk for BP5
and other recent studies,14
after adjusting for confounding factors, there were no between-group differences in the rates of MDD in the offspring. Bottom-up family studies have also shown that the first-degree relatives of youth with BP have significantly more depression when compared with first-degree relatives of healthy children48-50
but not when compared with the first-degree relatives of children with non-BP disorders.49,50,57
rates of depression increased during adolescence. Because BP may manifest its first symptoms with depression (30.0% in BIOS),3,60-63
particularly if there is family history of BP,61,64-66
it is likely that a significant proportion of the depressed children of parents with BP included in this study will eventually develop BP.
After adjusting for confounding factors, the offspring of parents with BP showed significantly higher rates of anxiety disorders, particularly generalized anxiety disorder, social phobia, and/or separation anxiety disorder, when compared with the offspring of control parents. There were no differences in the rates of other anxiety disorders, but the base rate of these disorders was low. Other studies of high risk for BP and studies of adults and youth with BP have also reported high rates of anxiety disorders.7,9,67-73
Also, high rates of anxiety disorders have been consistently observed in adults with early-onset BP when compared with adults with late-onset BP,1,70,71
and anxiety disorders appear to be associated with increased risk of developing BP during adulthood.44,74,75
Ongoing prospective follow-up of children recruited into BIOS will help to address this question.
High rates of DBDs and ADHD have been reported in offspring of parents with BP when compared with offspring of healthy parents5,9,16
and parents with non-BP disorders.11
Because some of the symptoms of these disorders overlap with the symptoms of BP69
and because mood disorders in youth are often manifested by severe irritability, ADHD-like symptoms, and oppositional behaviors, the earlier-noted findings have suggested that these symptoms may be one of the ways BP is manifested early in life or may be prodromal symptoms of BP.14,76-78
In BIOS, initial analyses also showed significant differences in the rates of DBDs, oppositional defiant disorder, and ADHD between the offspring of parents with BP and control parents. However, after adjusting for confounding variables, there were differences only in the rate of DBDs between offspring of parents with BP and healthy parents but not between offspring of parents with BP and control parents with non-BP psychopathology (). Thus, the presence of DBDs in the offspring of parents with BP seems to be related to general parental psychopathology or other related factors.
Of note, offspring of parents with BP with high SES showed more DBDs and any Axis I disorders than offspring of control parents with high SES. Because low SES has been associated with higher risk for childhood psychopathology, particularly behavior disorders,79
it is possible that higher SES is not protective in offspring of parents with BP. Alternatively, low SES may be such a strong predictor of DBDs that having a parent with BP confers no further risk of DBDs among subjects with low SES. Follow-up of the BIOS sample will further clarify whether early symptoms of ADHD and DBDs in offspring of parents with BP are early indicators for BP, particularly if these symptoms are severe.80
The rates of substance abuse for all of the offspring groups were relatively low, but most of the youth had not yet reached the age of highest risk for substance abuse. Youth with BP appear to be at higher risk for developing substance abuse than youth with other psychopathology.81,82
Moreover, substance use may lower the threshold for BP.83
Thus, early detection and treatment of these children are warranted before they develop substance use or abuse.
Taken together, our findings from BIOS have several potential clinical implications. Clinicians who treat adults with BP should question those who are parents about their children's psychopathology to offer prompt identification and early interventions for any psychiatric problems that may be affecting the children's functioning, particularly early-onset BP. Some of the psychopathology presenting in offspring of parents with BP, particularly depression and anxiety, could be associated with the development of BP. However, it is not clear what the optimal treatment would be, given the possible risk of antidepressants inducing the onset of BP in these high-risk children. Also, clinicians who treat offspring of parents with BP should be alerted to parental psychopathology because as shown in this and other studies,1
their parents may have other comorbid disorders besides BP that could convey negative implications for the children's longitudinal outcomes. Effective treatment of these parents may diminish and perhaps prevent psychopathology in their children.84,85
Because nearly half of the offspring of parents with BP have not yet manifested any diagnosable psychiatric illness, there is a great need and opportunity for primary prevention in this high-risk population. Thus, it is critical to have prospective longitudinal studies of the offspring of parents with BP that include comparisons with offspring of parents with and without non-BP disorders to evaluate clinical and biological phenotypes and genetic polymorphisms that can help determine who is at risk to develop BP.