Lithium has been one of the most-prescribed treatments for bipolar mania since its FDA approval in 1970. Many with bipolar disorder rely on lithium to stabilize their mood long-term, but the treatment may produce serious side effects, particularly if blood levels become imbalanced or with prolonged use. If safer mood stabilizers could be developed, many afflicted people would benefit.
Jean-Martin Beaulieu, Ph.D., Associate Professor of Psychiatry and Neurosciences at the University of Toronto, and winner of the 2014 One Mind / Johnson & Johnson Rising Star Translational Research Award, is building on his previous discoveries to generate and test the efficacy of specific, novel small molecules to remedy manic-like behavior in mice. Because these molecules are precisely targeted to act on one of lithium’s main therapeutic mechanisms, they replicate the therapeutic effect of lithium while potentially minimizing side effects. And, his team’s investigations are revealing a deep understanding of how all mood stabilizers work, opening new paths for even safer medications for bipolar disorder.
Building a Better Lithium
Beaulieu’s previous research has revealed the chemical process behind one of lithium’s known means of therapeutic action, the inhibition in the brain of a protein, GSK-3, which is involved in inflammation and cell death. By experimentally determining that this inhibition depends on lithium’s disruption of the interface between two enabling proteins, Akt and beta-arrestin2 (Ã__Arr2), Beaulieu and his team uncovered a new frontier for mood stabilizer development: targeting of the Akt/Ã__Arr2 interface. Their original hypothesis: Small molecules which selectively block the interface between the proteins Akt and Ã__Arr2 may be able to replicate the therapeutic effect of lithium in a much more benign way.
In 2015, Beaulieu’s team began to confirm this hypothesis. Testing the effect of a specific Akt/Ã__Arr2-disrupting protein, his team observed that it replicated the effects of lithium on Akt in the mouse brain. And, they found behavioral changes in these mice that mirrored some of the therapeutic effects of lithium.
Furthermore, they confirmed that the Akt/Ã__Arr2 interface is basic to the therapeutic action of two other mood stabilizers, lamotrigine, and valproate. And, they traced this mechanism of action to find that it influences the schizophrenia risk gene FXR1P, suggesting that these drugs might affect brain development relevant to a variety of psychiatric conditions.
Assisting the Brain’s Natural Balance?
Investigating further in 2016, Beaulieu’s team has now discovered evidence suggesting an even deeper explanation for these mood-stabilizing drugs efficacy: they appear to regulate homeostatic plasticity, a natural process of neurodevelopment that helps the brain’s circuit activities stay in balance.
By strengthening homeostatic plasticity, could future medications that target the Akt/Ã__Arr2 interface help keep the brain stable under clinically severely stressful circumstances? In 2017, Beaulieu and his team will test lithium and the novel molecules they have developed to characterize their influence on homeostatic plasticity.
A Star that Keeps Rising
The potential of the Beaulieu team’s Rising Star Award-funded science has earned them a major grant in 2016 from CQDM and Brain Canada, to develop a drug assessment process to help pharmaceutical and biotech companies rapidly discover new medications, to ultimately help those living with bipolar disorder.
We at One Mind congratulate Dr. Beaulieu on his exciting discoveries and are grateful to our donors for enabling us to fund this leading scientist.