There have been several reviews of studies of heterogeneous groups of bipolar parents and their offspring, largely cross-sectional in nature; that is findings based on a single assessment of lifetime psychopathology (for reviews see (Hodgins et al., 2002
; Lapalme et al., 1997
; DelBello & Geller, 2001
). Most of these studies have reported an elevated rate of a broad range of lifetime psychiatric disorders among offspring including mood, anxiety and substance use disorders, as well as high rates of comorbidity. Some studies have found an elevated rate of attention deficit disorder (ADHD) and behavioural disorders (Chang et al., 2000
), while others have not (Hillegers et al., 2005
). A recent large cross-sectional study of high risk and control offspring reported that, after adjusting for confounding variables (i.e. socioeconomic status, psychiatric disorder in the non-proband parent, within family correlations), there was no elevated rate of ADHD in the overall high risk group compared to controls (Birmaher et al., 2009
Despite the growing number of high risk studies, few have reported repeated longitudinal assessments of the same offspring over time and development. This likely reflects the fact that longitudinal studies are difficult and expensive to conduct. They are difficult to conduct because you need to engage and maintain contact with the families (parents and offspring) in order to communicate the findings and their relevance in order to encourage continued motivation, you must compete for research funding to ensure continuity with the families and with research staff and you must make a commitment to stay geographically local, with the flexibility of travel to reassess mobile offspring (away at university or in the event of family moves). These are not easy tasks in a large country like Canada, with relatively inadequate research funding (many outstanding competitors chasing few grant dollars), and limited funding terms (2 to 3 to 5 years terms). In spite of these challenges, there are four longitudinal high risk studies, in addition to the one I have been leading over the last 15 years.
Akiskal and colleagues described the course of psychopathology on average over a 3 year period in the clinically referred offspring or siblings of patients followed in their mood disorders subspecialty clinic (Akiskal et al., 1985
). The proband bipolar patients were well known to the research team and expertly diagnosed; which is not a trivial point given that the validity of high risk studies begins with the accuracy of diagnosis in the parent. These referred young relatives (mostly adolescents), presented with neurotic (anxiety) disorders and mood disturbances (dysthymia, cyclothymia) and then went on to develop major mood episodes including major depression and hypomania. No referred youth developed mania prior to adolescence.
Subsequently, Hammen and colleagues reported an important study comparing outcomes up to 3 years among the offspring of women diagnosed with either unipolar depression, BD, chronic medical illness or no illness (controls) (Hammen et al., 1990
). Children of bipolar mothers tended to develop anxiety and mild depressive disorders and functioned generally much better than the children of depressed mothers. However, activated symptoms below diagnostic threshold were observed in a few cases and the offspring of bipolar mothers were seen to develop more significant psychopathology later in development (adolescence). Again, there were no cases of prepubertal mania identified.
More recently, a Dutch research team, described psychopathological outcomes in offspring of bipolar parents over 5 years of prospective follow-up (Hillegers et al., 2005
). The parents were conservatively diagnosed and the majority of these families were recruited from the community. The offspring developed an elevated rate of mood disorders, debuting most often with major depression. There were no cases of prepubertal mania, and activated episodes tended to onset several years following the first major depressive episode. There was no elevated rate of ADHD or behavioural disorders in this high risk cohort. Furthermore, the offspring of bipolar parents had comparable attachment and social functioning to controls, however following the onset of illness there were associated changes and impairment in these domains (Reichart et al., 2007
; Reichart et al., 2009
Finally, among the offspring of Amish bipolar probands previously identified for genetic studies, Shaw and colleagues studied the first reliable symptoms of impending BD (Shaw et al., 2005
). Findings demonstrated that non-specific symptoms including anxiety and sleep problems later develop into activated, cognitive (distractibility) and mood symptoms and that these harbingers occurred episodically among the high risk offspring compared to controls. The episodic nature of BD is arguably the most characteristic feature of the illness (Angst & Marneros, 2001
; Grof et al., 1995
). Of note, there was no single case of prepubertal mania nor was there an elevated rate of ADHD or behavioural disorder in these high risk offspring.
In our own high risk study, we attempted to control for the effects of assortative mating and heterogeneity on psychopathological outcome and on the early course of mood disorder. Specifically, we limited inclusion to families in which there was one expertly diagnosed bipolar parent (based on a wealth of longitudinal clinical information) and one confirmed well parent (no lifetime major psychiatric illness) (Duffy et al., 1998
; Duffy et al., 2002
; Duffy et al., 2007a
). Given that we treated these parents systematically in a clinical research environment, we were also able to divide the parents into unequivocal lithium responders or non-responders based on a research protocol described elsewhere (Turecki et al., 1998
). There is convergent data showing that long-term response to lithium monotherapy (over 3 years minimum after a highly recurrent pre-treatment course), identifies a homogenous subtype of BD with characteristic genetic and neurobiological characteristics (Alda, 2004
; Grof P., 2009
; Mamdani et al., 2008
; Kruger et al., 2006
Over 15 years, we were able to show that despite controlling for assortative mating and heterogeneity of bipolar subtypes, offspring from both high risk groups manifest a broad range of psychopathological conditions. Furthermore, we found evidence that BD evolves in predictable clinical stages from non-specific anxiety and sleep disorders, to subthreshold mood disturbances and sensitivity to stress (adjustment disorders) and then starting in adolescence major mood episodes, typically depression (Duffy et al., 2009b
please see ). While not all offspring developed all stages, the sequence was the same in the majority of cases. Once major mood episodes started, they recurred into adulthood (Duffy et al., 2009a
We, like other groups, did not find any diagnosable cases of prepubertal mania. While ADHD was not elevated in the whole group compared to controls, it was elevated among the offspring of lithium non-responders as were other precursors including cluster A traits, learning disabilities and psychosis (Duffy et al., 2007a
). This suggested to us that in a subgroup of offspring from atypical parents, there may be a neurodevelopmental overlap similar to that seen in children at risk for psychotic disorders (Sigurdsson et al., 1999