NARSAD Young Investigator Melanie Carless, Ph.D., at Southwest Foundation for Biomedical Research is working on a breakthrough in process – she has designed a study to investigate gene expression differences between individuals with bipolar I disorder and their unaffected siblings or control subjects using blood cells (rather than deceased brain tissue), magnetic resonance imaging (MRI) techniques and in-depth questionnaires.

Mood disorders are considered to be one of the leading causes of disability worldwide, and are associated with a significant social and economic burden. Of these, bipolar I disorder represents a condition where extreme mood swings can occur, alternating between states of mania and depression, and may sometimes be accompanied by psychosis. Although bipolar I disorder is widely studied, progress in understanding the mechanisms by which it develops and how it may be better treated are hindered by the genetic complexity and clinical variability associated with the disease.

Dr. Carless’ study, done in cooperation with NARSAD Young Investigator, David Glahn, Ph.D., Department of Psychiatry, Yale University, examines two subsets of individuals: those with psychosis and those without. By examining changes in gene expression within blood cells, Dr. Carless and team are able to study a larger number of individuals, compare gene expression to unaffected family members, and study brain structure and function of each individual. They are using magnetic resonance imaging (MRI) techniques to determine brain volume and thickness, and they administer a questionnaire to assess general cognitive functioning, processing speed, memory and state-of-mind.

To date, the expression of approximately 24,000 known genes for 30 bipolar I disorder patients (15 with psychosis, 15 without), 25 unaffected siblings and 15 control subjects have been assessed. Although only a small number of samples have been analyzed, Dr. Carless is already seeing some promising results:

· When comparing bipolar I disorder patients without psychosis to control subjects, there is a significant over-representation of genes involved in regulating a particular type of cell (microglia) within the brain, reinforcing the recent hypothesis that it is linked to the manifestation of bipolar I disorder.

· When bipolar I disorder patients with psychosis were compared with those without psychosis, an over-representation of genes involved in release of a hormone (norepinephrine) that is well associated with the “fight or flight” response is observed. This hormone has been thought to be linked to psychosis and cognitive function.

· Also in individuals with psychosis, versus those without, a number of genes involved in the release of reactive oxygen species, which help fight cellular damage, showed differential gene expression, potentially implicating a novel pathway in the development of psychosis.

By identifying genes whose expression levels are altered in the blood cells of individuals with bipolar I disorder, Dr. Carless can begin to understand how such a complex disorder can develop. By increasing sample sizes, and assessing brain structure and function, Dr. Carless will gain more insight into the genes that regulate bipolar I disorder development and will therefore be able to identify potential targets for novel, and more effective, drug therapies.