Molecular Mechanisms Underlying Mood Stabilization in Bipolar Disorder

Lay Summary

Molecular Mechanisms Underlying Mood Stabilization in Bipolar Disorder

Through this pilot study, investigators will determine the feasibility of identifying molecular targets of the mood-stabilizing drug lithium in acutely ill patients with bi-polar disorder which may serve as biomarkers for testing potential new drugs.

Lithium is the current standard of treatment for patients with bi-polar disease. While the drug is known to induce multiple biochemical and molecular effects—including actions on cells’ signaling, hormonal regulation and gene expression—scientists do not yet know exactly how lithium exerts its therapeutic effects. Understanding this may lead to development of more effective treatments with less serious side effects. The investigators will undertake a pilot study in patients with acute bi-polar disease and healthy volunteer participants (controls) to determine if it is feasible to identify lithium’s molecular targets for stabilizing mood.  Prior animal research has identified nine potential molecular targets that may be sensitive to lithium’s actions. These nine molecules are thought to be present in the brain’s limbic regions that are believed to play a central role in regulating emotions. Additionally, growing evidence, from animal studies suggests that these same molecules also may be present in the tissue that lines the nose (olfactory epithelium), based on the understanding that these two structures undergo development at the same time in the embryo.  While it is not feasible to correlate actions of molecules with behavioral changes in the animal model, it would be possible to do so in patients.

In collaboration with researchers at Johns Hopkins University over the next two years, therefore, the Howard University investigators will study olfactory epithelium tissue biopsies in 16 patients with bi-polar disease undergoing lithium treatment for six weeks. They first will determine whether some or all of the nine candidate molecular lithium targets are found in patients’ olfactory epithelium tissue.  Next, they  will determine whether changes occur in those molecules after patients undergo six weeks of lithium therapy.  They then will assess whether the changes are associated with remission of patients’ mania and/or depression. If investigators find that molecules have changed only in patients and not in the eight control participants, the evidence would suggest that lithium is acting on those molecules.  If so, these molecules may serve as biomarkers of the disease..Additionally, the researchers will undertake genetic studies to develop initial data on genes that may be involved in producing these molecules, to begin to try to develop predictors of the risk of developing bi-polar disease. The findings are anticipated to lead to large-scale studies funded by others to confirm the biomarkers and to further explore genetic predictors of disease risk.

Significance:  Identification of biomarkers could lead to improved treatment for bi-polar disease, by enabling scientists to discover new experimental therapies that target these molecules more effectively and with fewer side-effects than lithium.