Early Risk Factors for Bipolar Disorder Found in Offspring of BD Parents

Although the diagnostic criteria for bipolar disorder (BD) include at least 1 manic episode (bipolar I) or 1 hypomanic episode and 1 major depressive episode (bipolar II), findings from prospective studies suggest that those with BD  may experience depressive episodes and other clinically significant psychopathology well before the first manic or hypomanic episode occurs.¹ In addition, the length of time between manic or hypomanic onset and diagnosis is estimated to exceed 10 years.

“This diagnostic delay is associated with devastating consequences including inappropriate treatment, increased hospitalization, medical comorbidity, treatment refractoriness, addiction, school dropout, underemployment, and suicide,” according to a narrative review published in 2017 in the International Journal of Bipolar Disorders.¹ To facilitate early detection of emergent BD, it is important to identify risk markers over the course of disease development. Prospective studies of high-risk offspring of individuals with BD could provide valuable insights in this area.

“This design allows for parallel, real-time assessment of risk factors and potential confounds — allowing for the separation of trait from state, critical to the task of identifying risk markers and endophenotypes,” wrote the review authors. “Ultimately, this advance will inform the development and timing of specific early interventions; thereby reducing the proportion of individuals reaching end-stage illness and [development of] a progressive illness course.”¹

Their review of studies on the topic produced the following observations:

• The most robust predictive risk factor for BD is a confirmed history of the illness in a first-degree relative, which is associated with an 8-fold to 10-fold lifetime risk for BD and a 2-fold to 3-fold lifetime risk for depressive disorder vs the general population.¹
• Factors that may further increase individual risk include “high penetrance across multiple generations, an earlier age of onset in the proband bipolar patient, and assortative mating,” as noted in the review. “Additionally, early adversity in the form of abuse, neglect, increased exposure to active parental illness, and attachment difficulties have been associated with an increased risk and an earlier age of onset of bipolar disorder, possibly through epigenetic mechanisms.”¹
• In children with confirmed familial risk, childhood anxiety and sleep disorders are linked with a 2.5-fold to 3-fold increased risk for major mood disorders compared with high-risk offspring who do not exhibit these features.¹
• Multiple offspring studies have demonstrated the prominence of depressive mood disorders early in the trajectory of emergent BD, often appearing in early to mid adolescence.^2-4
• Based on an analysis² of the Flourish Canadian prospective offspring cohort study,⁵ the best-fit model of the trajectory of emerging BD “supported a shift from nonspecific childhood antecedent syndromes (ie, sleep problems, anxiety, and in the lithium nonresponsive bipolar subtype, neurodevelopmental disorders) to internalizing symptoms under stress (ie, sensitivity), to depressive disorders and finally on to the manifestation of the first activated episode,” explained the authors of the 2017 paper.¹

They concluded that results of such studies could lead to improved strategies for diagnosis and treatment, including a more comprehensive diagnostic approach that considers the predictive risk factors described above, and “early intervention programs that provide timely expert assessment and evidence-based care to those with emergent illness, especially those with a confirmed familial risk of major psychiatric illness and/or suicide.”¹

To further discuss the implications and remaining research needs in this area, Psychiatry Advisor spoke with one of the authors of the review, Anne Duffy, MSc, MD, FRCP(C), professor of psychiatry at Queen’s University in Ontario.

Psychiatry Advisor: What is known thus far about the early illness course of BD, and what are the clinical implications of your findings and those of other researchers?

Dr Duffy: There have been a number of studies mapping the onset and early course of BD in the offspring of affected parents. These studies, including our own, have highlighted that children of parents [with bipolar disorder] are an important identifiable high-risk group who would benefit from surveillance clinically, and that anxiety and sleep disorders in these children predict subsequent mood disorders.

In addition, these studies have underscored the importance of major depression in the early course of BD. Finally, family history is an important predictor of BD and gives meaning to relatively otherwise nonspecific antecedent psychopathology — we should be regularly using family history in our diagnostic and risk assessments.

Psychiatry Advisor: What are the broader implications pertaining to diagnosis or otherwise?

Dr Duffy: Psychiatric diagnosis is at an important crossroads. The [Diagnostic and Statistical Manual of Mental Disorders] is clearly too broad for mapping the origins of illness and discerning between illnesses. We should incorporate all available predictive information in our diagnostic determinations, including developmental history, clinical course, family history, and any known risk exposures/context. This is what led to advancements in other areas of medicine.

Psychiatry Advisor: What should be the focus of future research in this area?

Dr Duffy: [Future studies should attempt] to map trajectories of more homogeneous subtypes of BD and map the evolution of illness at multiple levels simultaneously, including genetic/epigenetic, neurobehavioral, psychological, and clinical.

References

1. Duffy A, Vandeleur C, Heffer N, Preisig M. The clinical trajectory of emerging bipolar disorder among the high-risk offspring of bipolar parents: current understanding and future considerations. Int J Bipolar Disord. 2017;5:37.
2. Duffy A, Horrocks J, Doucette S, Keown-Stoneman C, McCloskey S, Grof P. The developmental trajectory of bipolar disorder. Br J Psychiatry. 2014;204(2):122-128.
3. Mesman E, Nolen WA, Reichart CG, Wals M, Hillegers MH. The Dutch bipolar offspring study: 12-year follow-up. Am J Psychiatry. 2013;170(5):542-549.
4. Nurnberger JI Jr, McInnis M, Reich W, et al. A high-risk study of bipolar disorder. Childhood clinical phenotypes as precursors of major mood disorders. Arch Gen Psychiatry. 2011;68(10):1012-1020.
5. Goodday S, Levy A, Flowerdew G, et al. Early exposure to parental bipolar disorder and risk of mood disorder: the Flourish Canadian prospective offspring cohort study. Early Interv Psychiatry. 2018;12(2):160-168.