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Even though it was introduced more than fifty years ago as a treatment for bipolar disease lithium remains an enigma. It is one of the few medicines that retains its place as the main therapy for treating its targeted disease over the course of its lengthy life. But no one knows for sure how it works.

The reasons behind this mystery are what drive researchers at the ӳ����ý’s Stanley Center to pin down lithium’s mechanism of action. What molecule(s) does it target in the body? No one really knows for sure. Yet, we know that half of the people who take lithium for bipolar disorder respond to it with at least some improvements in symptoms. But what explains the other half who do not respond?

Both of these questions are addressed in a recent Neuropsychopharmacology from Stanley Center investigators and colleagues.

It is actually a chemical salt of lithium that is prescribed for mood stabilization in patients with bipolar disease. Researchers have thought at least part of its effect may be due to its action on an enzyme called glycogen synthase kinase-3 (GSK-3β). For more than ten years, researchers elsewhere have been studying GSK-3β in the context of diabetes, and more recently, in cancer. But only recently have researchers started looking at how the enzyme may relate to bipolar disorder

ӳ����ý researchers first needed to develop chemical and genetic tools that would allow them to see if GSK-3β is a relevant lithium target. The team first developed a cell culture system that mimics differences in lithium sensitivity—some cell lines responded to lithium and others did not. They next tested a range of GSK-3β inhibitors in lithium-sensitive cell lines and found that they did indeed act like lithium. Going further, the researchers tested one particular inhibitor in mice and again found that blocking GSK-3β produced lithium-like results. These findings confirm that GSK-3β is involved in lithium’s activity but it does not mean that other targets are not involved in lithium’s mood stabilizing effects.

But why are some cells and mice resistant to lithium? Could its activity be restored? It turns out that adding an activated form of an enzyme called AKT1 to the lithium-resistant cell lines could restore their sensitivity. The big experiment was to see if they could do the same in mice. Yes, again. Lithium sensitivity was restored in the mice by injecting a virus that enables the expression of activated AKT1 into a particular area of the brain.

These results represent a significant step forward in the study of biochemical pathways involved in bipolar disease. “Having a connection between the cellular assay and an in vivo study in a living organism is a huge step forward in the field of psychiatry,” explains Stephen Haggarty, director of Chemical Neurobiology at the Stanley Center. “To be able to have a cellular and physiological system that provides a way to study the GSK-3β pathway and others is going to provide new avenues for developing more insight into how lithium works and eventually to other therapeutics.”

Working with colleagues in the ӳ����ý’s Chemical Biology Platform, the Stanley Center team has already set to the task of developing new GSK-3β inhibitors that enhance the effects of lithium. “If we could reduce the dose of lithium a patient needs that could actually have a significant clinical impact,” explains Jen Q Pan, first author of the paper and group leader in the Stanley Center. ”Plus the targets of those molecules might provide insight into how lithium really works.”

The joint team is also collaborating on a large effort to find, develop, and optimize better GSK-3β inhibitors. All of the work done in this project is publicly available as the molecules were all screened by the ӳ����ý’s Probe Development Center, part of the NIH’s MLPCN, which offers access to hundreds of thousands of chemical compounds that can be used as tools to probe basic biology and advance our understanding of disease.

In collaboration with researchers and clinicians from MGH and McLean Hospitals, one of the most exciting new directions this project is taking involves taking advantage of advances in stem cell technology that will allow the team to probe GSK-3β signaling in human neurons derived from patients with bipolar disorder. Says Haggarty, “By bringing human genetics into the picture, we envision gaining new insight into what lithium does and finding ways to mimic and hopefully improve this to advance the treatment and understanding of bipolar disorder.”