Vol. 28 – Juvenile Bipolar Disorder – Progress in Research III

This is the last of a three-part series to inform you about the findings from research studies funded by the Juvenile Research Foundation. The first two Newsletters described the approach and development of a new perspective on pediatric bipolar disorder. This Newsletter tells you about the direction that researchers plan to follow now that the foundation for this novel view is in place. We hope you will be encouraged by the progress and inspired to believe that the end of this journey is attainable.

The research that we have brought to your attention is well poised to move on to the next phase of investigation. The specificity and accuracy with which a subtype of the illness has been defined improves the chances of success for ensuing studies. To summarize the work to date, researchers supported by the Juvenile Bipolar Research Foundation (JBRF) has collected clinical information on a large sample of children who have been diagnosed or are suspected of having pediatric bipolar disorder. Multiple analyses run on this data generated the following:

• The delineation of a genetically robust trait called Fear-of-Harm (FOH) that serves to define a subtype of the illness which has become the focus of our investigation.
• A highly specific dimensional symptom profile that accompanies the FOH trait.

This highly heritable trait makes it an ideal candidate for further genetic study and the dimensional symptom profile points us to very specific brain pathways that may explain the biological underpinnings of this subtype. The dimensional symptom profile also allows us to identify, with 96% accuracy, children who have the trait. This is an enormous improvement over the current state of affairs and finally moves us down a path that could potentially yield more targeted treatment strategies, including pharmacological, psychological and circadian approaches.

To continue to focus on this single, hereditary behavior as the basis for future studies undoubtedly leaves some children who exhibit a bipolar disorder out of the mix. However, given the complexity of the physiology involved, this dissection of the illness into a very specific slice is necessary. This is the route that may better enable researchers to uncover real and useful answers.

This single behavioral trait is not uncommon. Some degree of the FOH trait was found to be present in 2/3 of the study population. A full 1/3 of the subjects exhibited the trait in its pure form. So, while it does not cover all children, it is very relevant and conclusions drawn from it are likely to have wide application.

The compilation of evidence-based not conceptual information is key to the development of a broad-based body of knowledge that can move the research agenda forward. Listed below are the three main research areas that researchers now plan to pursue as this strong foundation of inquiry has been established.

Genome-wide Association Study

Identification of susceptibility genes for bipolar disorder is the most direct way to discover the network of signaling pathways in the brain that regulate specific behaviors associated with the condition. The development of treatments which specifically target those pathways can then be launched.

In a technique called genome wide association study (GWAS), investigators scan the entire human DNA, or genome, of many individuals to pick up genetic variations that differ between healthy individuals and individuals with the disorder of interest.

Of critical importance to the success of this approach is: 1) the selected cases should be homogeneous for the target condition, and 2) the sample size must be large enough to provide statistically significant results.

We believe that the delineation of the FOH trait and the dimensional, clinical profile of symptoms associated with it will potentially allow us to gather such a homogeneous group. The ease and accuracy that the Child Bipolar Questionnaire brings to the identification of children with the FOH trait promises to round up the very large sample of cases needed to proceed with the scan. JBRF has already made substantial progress in the process of collecting DNA samples from children who fit the FOH trait. We need your participation to gather as many samples as possible. A link for this purpose is at the end of this News Flash.

Chronobiology Biomarker Study

Chronobiology is the study of biological rhythms. A biomarker is a distinctive biological indicator of a process, event, or condition. The identification of a biomarker for a specific condition greatly enhances diagnostic reliability and simultaneously identifies a treatment target that may reduce the impact of the condition. In this study, investigators seek to explore the relationship between sleep/activity patterns and thermal regulation in children with the FOH subtype to determine if some imbalance in the relationship between these rhythms could be a biomarker of the illness.

Preliminary studies and longstanding clinical observations tell us that many children at risk for, or who carry a diagnosis of, pediatric bipolar disorder experience numerous types of sleep disturbances as well as a dysregulation of activity rhythms. They also feel excessively cold in the mornings, overheat in the evenings, have a poor thermogenic response to cold, and sweat profusely during even mild physical exercise. Dimensional analysis revealed that these phenomenons are represented as parts of behavioral dimensions that accompany the FOH trait. Since we know that the relationship between core and outside body temperature interact with the circadian rhythm of sleep, the onset and offset of sleep as well as the quality of sleep, the dysregulation of this relationship may well be a biomarker of the condition.

Investigators have launched a study, funded by the National Institute of Mental Health (NIMH), to explore this phenomenon. While the study is ongoing, preliminary results indicate that this could indeed turn out to be a biomarker for the illness. What’s more, the underlying physiology involved in the core versus outside body temperature relationship also influences other dimensions of the illness such as anxiety, aggression, sweet cravings, and fear conditioning.

Stem Cell Study: Turning Skin Cells into Brain Cells

In a remarkable new process that is only three years old, investigators have the capability to deprogram a skin cell, return it back to its original stem cell state and then encourage it to develop again down a completely different developmental path into a brain cell or “neuron”. This novel procedure will allow researchers to examine differences in gene expression in brain cells through a direct comparison of the DNA of an individual with pediatric bipolar disorder and a control subject.

This process could tell us all sorts of things about how that brain cell functions or malfunctions and how it will respond in the presence of different medications. Using the FOH phenotype to identify a clinically homogeneous group of children that represent a subtype of the illness, investigators are hopeful that they will achieve meaningful results.

We hope you have found this discussion interesting and inspiring. We feel that the research conducted so far has done a lot to correct a fundamental obstacle that prevented the timely progression of research and development. We look forward to the mounting body of useful information that this new approach opens up. Together we can find ourselves further down the path to peace that we and our children so desperately desire.

Alissa Bronsteen and Demitri Papolos, M.D.