Anxiety and Depressive Disorders Often Precede the Onset of Bipolar Disorder in Those At High Risk Due to Family History

January 23, 2013 · Posted in Course of Illness, Risk Factors 


At the 2012 meeting of the American Academy of Child and Adolescent Psychiatry (AACAP) meeting, Anne Duffy and Gabrielle A. Carlson sponsored a symposium on the association between anxiety and minor mood disorders and subsequent bipolar disorder in those at high risk. Researchers presenting at the symposium consistently found that there is a sequence in which young people at high risk for bipolar disorder develop increasingly severe illnesses: first anxiety, then mood disorders, then bipolar illness.

One difference: the incidence of childhood-onset bipolar disorders in those at high risk because a parent has the disorder was lower in Canada, Switzerland, and the Netherlands than it was in the US.

Duffy, a professor of psychiatry in Calgary, noted that bipolar disorder is highly heritable even though most adults with bipolar illness do not have a family history of bipolar illness among their first-degree relatives. She shared estimates that if one parent has bipolar disorder their offspring have a 5% lifetime risk of developing bipolar disorder. If both parents have bipolar disorder their offspring have a 25% risk of developing bipolar disorder and a 35% incidence of developing any affective disorder (although other data by Lapalme et al. suggest it may be as high as 60%).

Duffy found that when parents responded well to lithium, their children tended to do the same. Lithium-responsive patients tended to be those without anxiety disorder and substance abuse and who had classic bipolar episodes and clear well intervals between episodes.

In her sample of Canadian patients, Duffy found that a sequence of developing anxiety and mood disorders seemed to predate the onset of bipolar disorder in those at high risk because a parent has bipolar disorder. Anxiety disorders were the first to occur, at a mean age of 8. These were followed by minor mood disorders in adolescence, then major depression in late adolescence or early adulthood, and finally bipolar disorder. Among the anxiety disorders, social phobia, panic, and generalized anxiety disorders were significant predictors of subsequent bipolarity and generalized anxiety disorder was an independent predictor of subsequent bipolarity.

Researcher Martin Preisig discussed a Swiss study of children at high risk for bipolar disorder due to having a parent with the disorder. The study took place in Lausanne and Geneva and included 134 offspring of a bipolar parent, 107 offspring of a parent with major depression, and 106 offspring of controls who had orthopedic medical problems. As expected, the incidence of any mood disorder was much higher in the offspring of parents with bipolar illness or major depression. A mood disorder was diagnosed in 34.5% of the offspring of the bipolar parents and 25.5% of the offspring of the parents with a major depressive disorder, and only 12.6% of controls.

Interestingly, there was a low and nonsignificant difference in the incidence of bipolar disorder, with 3.6% occurring in the offspring of parents with bipolar disorder, 2.7% in the offspring of parents with a major depressive disorder, and 0% of the controls. Preisig also found that anxiety preceded depression, which preceded the appearance of mania. Anxiety emerged at a mean age of 10, followed by depression and then mania at a mean age of 15. If a child developed an anxiety disorder, they were three times more likely to develop bipolar disorder. However, depression was not a good predictor of bipolar disorder, and recurrent major depression seemed to occur more often in those with a parent with major depression compared to those with a parent with bipolar disorder.

Researcher David Axelson discussed a study of US children aged 6-18 from Pittsburgh, Los Angeles, and Providence. He compared 391 offspring of bipolar parents with 249 offspring of healthy parents. In contrast to the previous studies that were performed outside of the US, Axelson’s study found significantly higher incidence of bipolar disorder in the offspring of bipolar parents compared to controls, with an illness on the bipolar spectrum (bipolar 1, bipolar 2, or bipolar not otherwise specified (NOS)) occurring in 18.7% of the offspring of parents with bipolar disorder. Also in contrast to the previous presentations, he found that depression multiplied the risk of subsequent bipolar disorder by 11.7. The presence of an oppositional defiant disorder or attention deficit hyperactivity disorder (ADHD) multiplied the risk by 2.4.

Axelson found a high incidence of anxiety disorder comorbidity in the offspring of bipolar parents, particularly generalized anxiety disorder and panic disorder. ADHD was comorbid in 50% of the offspring of bipolar parents compared to 27% of the controls.

Substance abuse also occurred in 29% of the offspring of bipolar parents, a much higher rate than in controls. Substance abuse emerged after the onset of bipolar disorder in the majority of cases. This provides a window of many years to attempt to head off substance use with education and other methods of prevention in those with early onset bipolar disorder.

Among the offspring of parents with bipolar disorder, 10.7% had bipolar NOS, 4.1% had bipolar II and 3.6% had bipolar I. However, approximately 40% of the children diagnosed with bipolar NOS converted to bipolar I or II over several years of follow-up. The diagnosis of bipolar NOS was typically given because symptoms of mania lasted only one day (43%), 2 days (28%), or 3 days (30%). Thus, in the United States, mania of brief duration or hypomanic bursts are a common way the illness initially presents. Given these data and previous evidence that bipolar NOS is highly impairing, attempts to treat it and prevent or slow the development of more full-blown manic episodes are important. In summary Axelson suggested that two-thirds of the offspring of bipolar parents who experience a major depression ultimately became bipolar.

Manon Hillegers discussed a Dutch study of a cohort of children at high risk for bipolar disorder because of a parental history of the disorder. Hillegers’ research group also found that anxiety and depressive disorders occurred more commonly than bipolar disorder in the offspring of parents with bipolar disorder. Upon long-term follow-up, the researchers found that 19.5% of the offspring developed depression, while only 2.5% developed bipolar disorder, and of these, only four of the children developed the most severe variant, bipolar I. Following this cohort for 12 years, the researchers found that 54% of these children at high risk developed an affective disorder in that time.

Anne Glowinski discussed a study led by John Nurnberger that examined cohorts of American children at high risk for bipolar disorder. They found that 8.5% of these children at high risk developed a bipolar disorder compared to 0% in the control population. The children also showed substantially greater anxiety disorders, disruptive behavioral disorders, and substance abuse disorders. In contrast to the much later onsets of mania in the non-US cohorts noted above, Nurnberger’s research group found a mean age of onset of mania of 12.5 years. The presence of an anxiety disorder was a risk factor for earlier onset and higher incidence of onset of a bipolar disorder.

Editor’s Note: There was a great degree of agreement in these findings, although there were several important differences. All of the studies indicated that anxiety and depression tended to emerge prior to bipolar episodes in children at high risk by virtue of having a parent with bipolar disorder. However, in contrast to the low to negligible incidence of bipolar disorder in very young offspring from Canada, Switzerland, and the Netherlands, there was a substantial incidence of bipolar disorder in the young offspring of parents with bipolar disorder in the US in the two cohorts studied by Axelson and Nurnberger and colleagues. These data are consistent with others that we have reviewed in previous issues of the BNN that indicate that there is an earlier age of onset of bipolar disorder in the US compared to many European countries.

This editor (Robert Post) asked the panel members how they would treat an eight-year-old child with a serious anxiety disorder and two parents with bipolar disorder. Carlson and most of the other panelists indicated that they would use an antidepressant such as an selective serotonin reuptake inhibitor (SSRI), but there are no controlled data to guide decision making. Hillegers indicated that in the Netherlands they would use psychotherapy and cognitive behavioral psychotherapy rather than medication in a very anxious child of this age.

Duffy suggested she would use the parental history of response to pharmacotherapy as a guide to treatment of the offspring – lithium for lithium responders; anticonvulsants or atypical antipsychotics for lithium non-responders. This editor cited Duffy’s own data indicating that lamotrigine response runs in families and that this might be considered for anxiety/depression in a child at ultra-high risk for bipolar disorder by virtue of both parents having the disorder. Other options might be any of the other anticonvulsant mood stabilizers (valproate or carbamazepine), one of the well-tolerated atypical antipsychotics (quetiapine, aripiprazole, or lurasidone), the anti-anxiety drugs (clonazepam or gabapentin), or even omega-3 fatty acids and N-acetylcysteine.

The lack of any systematic data about the best treatment options for an anxious or depressed youth with a positive family history of bipolar disorder is another tragic example of the failure of funding agencies such as the National Institute of Mental Health (NIMH) and the Substance Abuse and Mental Health Services Administration (SAMSHA) to begin addressing the problems of children with or at risk for bipolar disorder.

Since all of the presenters agreed on the most usual sequence of anxiety followed by depression followed by bipolar disorder in children at high risk, the virtual absence of studies of treatments for these children or those who already have disabling bipolar NOS is disturbing. Throughout the entire AACAP meeting there was a general absence of studies on medications for any aspect of the recurrent mood and anxiety disorders, despite the recognition that most adult mood and anxiety disorders begin in childhood and adolescence.  Getting youth with serious mood and anxiety disorders on the right track early in their course of illness could have life saving implications.  What a shame that this opportunity is often lost because of a dearth of treatment research.


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