A Symposium on High Risk Studies: Offspring of Parents with Bipolar Disorder
In a symposium at the 2014 meeting of the International College of Neuropsychopharmacology, four researchers shared insights on children who are at higher risk for bipolar disorder because they have a parent with the disorder.
Researcher John Nurnberger has been studying 350 children of parents with bipolar disorder in the US and 141 control children of parents with no major psychiatric disorder, following the participants into adolescence. He found a major affective disorder in 23.4% of the children with parents who have bipolar disorder and 4.4% of the controls. Of the at-risk children, 8.5% had a bipolar diagnosis versus 0% of the controls.
Nurnberger found that disruptive behavior disorders preceded the onset of mood disorders, as did anxiety disorders. These diagnoses predicted the later onset of bipolar disorder in the at-risk children, but not in the controls. A mood disorder in early adolescence predicted a substance abuse disorder later in adolescence among those at risk.
In genome-wide association studies, the genes CACNA1C and ODZ4 are consistently associated with risk of bipolar disorder, but with a very small effect size. Therefore, Nurnberger used 33 different gene variants to generate a total risk score and found that this measure was modestly effective in identifying relative risk of developing bipolar disorder. He hopes that using this improved risk calculation along with family history and clinical variables will allow better prediction of the risk of bipolar onset in the near future.
Researcher Ann Duffy reported on her Canadian studies of children who have a parent with bipolar disorder and thus are at high risk for developing the disorder. In contrast to the studies of Nurnberger et al. and many others in American patients, she found almost no childhood onset of bipolar disorder before late adolescence or early adulthood. She found that anxiety disorders emerge first, followed by depression, and then only much later bipolar disorder. Bipolar disorder occurred with comorbid substance abuse disorders in only about 10-20% of cases in 1975, but substance abuse increased to 50% of bipolar cases in 2005. The incidence of comorbid substance disorder and the year at observation correlated strongly, indicating a trend toward increased substance abuse over the 30-year period.
Duffy found that having parents who were ill as opposed to recovered was associated with a more rapid onset of mood disorder in the offspring, usually in early adulthood. Duffy emphasized the need to intervene earlier in children of parents with bipolar disorder, but this is rarely done in clinical practice.
Duffy also reported that even in individuals doing well on lithium (without major mood fluctuations), there were were still fluctuations in cortisol and its ability to be suppressed by dexamethasone. She found that those with remitted bipolar disorder had the highest cortisol levels, at-risk offspring (who had not yet become ill) were intermediate, and controls the lowest.
Duffy quoted the 2013 data of researchers Baethage and Cassidy that among 10- to 24-year-olds, suicide was the second highest cause of death (accidents was first). Ninety percent of the suicides were related to mood disorders, with a high percentage being bipolar mixed, early onset, and associated with substance abuse.
Duffy also added to the growing literature on the high levels of the inflammatory marker Il-6 present in early stages of illness prior to the onset of bipolar disorder, with a decrement in Il-6 in later stages of full-blown bipolar disorder. Similar increases in the neurotrophic factor BDNF were seen in early stages, and decreases in later stages. There were also differences in these indices as a function of the common and better functioning val-66-val allele of proBDNF (which has been associated with early onset bipolar disorder) versus the met-66-met allele, which functions less well and has been associated with mild cognitive deficits in various populations. More details of this study were published in the International Journal of Bipolar Disorders in 2014.
Researcher Jan Scott discussed the 2011 study by Gore et al. that showed that bipolar disorder produced the fourth highest global burden of disease (with unipolar depression first, traffic accidents next, and schizophrenia third).
Scott also mentioned a study by Bruce Birmaher that showed that children with diagnoses of bipolar disorder not otherwise specified (NOS), when followed for several years, converted to full-blown BP I or BP II disorder 58.5% of the time when there was a family history of bipolar illness and 35.5% of the time when there was no family history of the illness.
Scott cited six studies of children at high risk who were treated with psychotherapy—two with family focused therapy (FFT), two with cognitive behavioral therapy (CBT), and two with interpersonal therapy (IPT). The results were promising across the board, and each therapy was endorsed along with psychoeducation (PE) and mindfulness training. These data support the utility of preventive psychotherapeutic intervention in children at high risk because of a family history of mood disorders.
Editor’s Note: In our own studies in the US, we found a high incidence of illness not only in the parents of patents with bipolar disorder, but also in the grandparents. Greater total illness across the two generations was associated with more complex illness in the patients. They not only had bipolar disorder, but also a higher incidence of early onset illness, anxiety and substance abuse comorbidity, more episodes, and rapid cycling. These data along with Scott’s review offer strong reasons to provide psychotherapy to those at very high risk due to having two generations of relatives with multiple illnesses.
Scott discussed the link between sleep disturbance and rumination in mood disorders. Sixty-two percent of patients with bipolar disorder have delayed onset sleep, versus 30% with unipolar depression, and 14% in controls. A ruminating coping style (as opposed to distraction, active coping, or risk-taking) was associated with poor sleep, high cortisol, low mood, and substance abuse.
Phillip Mitchell gave the final talk at the high-risk symposium. He explained that compared to control populations, at risk offspring of bipolar parents had increased odds ratios (between 1.3 to 3.9) of having an affective, anxiety, disruptive behavioral, or substance abuse disorder, or any two of these diagnoses. In patients who had already been diagnosed with bipolar disorder, the risk of having comorbidities was even higher. The odds ratios for the above comorbidities compared to the controls ranged from 6.2 to 9.7, and the odds ratio for having two or more diagnoses was 28-fold higher.
The at-risk offspring had other characteristics that more closely resembled the participants with bipolar disorder than the control participants without a family history of bipolar disorder, including: increased sleep in 66.7%, early onset of a mood or anxiety disorder before age 18 in 47.6%, and 33.3% with four or more atypical features to their depression, which included hypersomnia, hyperphagia, leaden paralysis, psychomotor retardation, psychosis, and mood fluctuations.
