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Symptoms Outdo Diagnoses in Predicting Bipolar Disorder in At-Risk Youth

Science Update

Three types of symptoms emerged as powerful predictors of whether a youth with one parent with bipolar disorder will go on to develop the disorder, according to a study of 391 at-risk youth. The findings offer a much more specific roadmap than previously available for assessing risk of bipolar disorder early in at-risk youth, and one that is based on symptoms, not traditional psychiatric diagnoses. The symptoms identified—related to anxiety/depression, affective lability (unstable mood, including irritability), and low-level manic symptoms—also provide insight into what may be a high-risk syndrome or “prodrome” preceding the onset of bipolar spectrum disorder.

People with bipolar disorder experience marked, often extreme shifts in mood and energy. The disorder affects an estimated 2.6 percent of Americans. Someone with bipolar disorder experiences periods of depression alternating with periods of mania, a state marked by high energy, overconfidence, and frantic activity. The mood swings can severely disrupt a person’s ability to function normally; as many as 15 percent of those affected die by suicide. Despite this, there are often years-long delays before an accurate diagnosis and appropriate treatment. Research has suggested that a bipolar prodrome might precede the emergence of bipolar disorder by several years; the hope is that identifying the features of the prodrome could help guide an understanding of how the disorder emerges, and enable earlier detection and more timely and effective treatment.

Scientists participating in the NIMH-funded Pittsburgh Bipolar Offspring Study (BIOS) recruited children of parents with bipolar disorder and a similar group of 248 youth with no family history of the condition. The BIOS team, at the University of Pittsburgh, followed both groups for an average of eight years, collecting information on symptoms of psychiatric disorders, including depression, anxiety, and attention-deficit hyperactivity disorder. While previous research had found that most people diagnosed with bipolar disorder recalled having symptoms of psychiatric disorders earlier, in order to determine accurately how preexisting symptoms affect risk for later development of a disorder, it’s necessary to study populations prospectively, or over time, starting years before a disorder emerges. This study looked at a relatively large at-risk population; by the end of the study 44 of the participant youth were diagnosed with bipolar disorder.

Previously, the study had reported  on categorical predictors of bipolar disorder—the presence or absence of a collection of symptoms on which a diagnosis is based—such as depression and subthreshold manic episodes. Among their findings was that, taking into account only results based on following youth over time, and not recall of past symptoms, only a previous episode of “subthreshold mania or hypomania”—defined on the basis of symptoms, functioning, and duration—predicted later development of bipolar disorder.

This more recently reported phase of the study, led by Danella M. Hafeman, M.D., Ph.D., and Boris Birmaher, M.D., took a different approach. This study looked at symptoms in different dimensions of function, without reference to umbrella diagnostic categories, and how these symptoms predicted bipolar spectrum disorder.

Levels of several different dimensional symptoms were higher in the high-risk youth when they were first evaluated, including those related to anxiety/depression, inattention/disinhibition, externalizing (disruptive and impulsive behavior), affective lability (unstable mood, including irritability), and low-level manic symptoms (not necessarily part of an episode). Symptom levels in three areas emerged as the strongest predictors of later bipolar disorder: anxiety/depression at baseline (as participants entered the study); affective lability, both at baseline and shortly before a bipolar diagnosis; and low-level manic symptoms shortly before diagnosis. Earlier age at which at which a parent was diagnosed with a mood disorder also increased risk. Youth with all four of those risk factors had a 49 percent chance of developing bipolar, vs. a 2 percent chance for those without them.

At the same time, it’s important to note that over half of those with all four of the most powerful risk factors did not develop bipolar disorder by the end of the study.

The risk factors identified in this study predicted the onset of bipolar disorder whether or not a young person also had a preexisting categorical diagnosis other than bipolar disorder. In fact, the report points out, once the dimensional risk factors were accounted for, disorders no longer predicted future bipolar disorder.

These findings offer an approach to assessing risk on the basis of symptoms without respect to diagnoses. These insights can inform clinical diagnosis, but also provides clues for researchers on the facets of the prodrome. Research suggests that changes are occurring in the brain well before psychiatric disorders like bipolar disorder and schizophrenia emerge with obvious symptoms. Information on this prodromal period can not only make early treatment possible, but could help scientists understand the origin of the brain changes with the aim of eventually being able to interrupt the process and prevent disease.

“This study is the first large effort to document the relevant prodromal factors for bipolar disorder in the context of an unfolding process across time,” said Shelli Avenevoli, Ph.D., acting NIMH deputy director. “It demonstrates the potential of combining dimensional symptoms and family risk to enhance risk prediction and for investigating the nature of the prodrome.”

Lead author Danella Hafeman, M.D., Ph.D., said, “The results of this study begin to define an ultra-high risk population, similar to the work that has been done in psychosis. The identification of such a population is important to clinical practice, identifying patients who might require increased surveillance, as well as future research to evaluate strategies for early intervention.”


Hafeman DM, Merranko J, Axelson D, Goldstein BI, Goldstein T, Monk K, Hickey MB, Sakolsky D, Diler R, Ivengar S, Brent D, Kupfer D, Birmaher B. Toward the Definition of a Bipolar Prodrome: Dimensional Predictors of Bipolar Spectrum Disorders in At-Risk Youths.  Am J Psychiatry. 2016 Feb 19:appiajp201515040414. [Epub ahead of print]