Neurology Central

Bipolar therapeutics: a unified model?

We recently featured the review ‘Inositol depletion, GSK3 inhibition and bipolar disorder’ from our partner journal, Future Neurology. This #NCMentalHealthMonth, we speak to the paper’s authors, Miriam Greenberg and Wenxi Yu, both from Wayne State University (WSA; WA, USA). The authors discuss the current hypotheses surrounding the therapeutic mechanisms of anti-bipolar drugs, as well as their hopes for the future of the field of bipolar disorder therapeutics.

First, please could you tell us a little about your research background and what led you to become interested in the therapeutic mechanisms of inositol-depleting drugs in bipolar disorder?

Miriam Greenberg: My interest in the importance of inositol stems from my graduate work in Susan Henry’s laboratory (Cornell University, NY, USA), in which I identified and characterized the first negative regulator of inositol synthesis in yeast. Dr Henry’s pioneering studies using the yeast model demonstrated that inositol plays a fundamental role in cellular function; remarkably, inositol supplementation of yeast cells triggers a global transcriptional response affecting hundreds of genes.  When I became an independent investigator, I was intrigued by Michael Berridge’s (Babraham Institute and the University of Cambridge, both UK) inositol depletion hypothesis regarding the therapeutic mechanism of lithium.  Based on the finding that lithium uncompetitively inhibits inositol monophosphatase, Berridge proposed that the therapeutic mechanism of lithium may result from attenuation of PI signaling due to inositol depletion.

This hypothesis was pivotal in stimulating many researchers, including myself, to investigate the cellular consequences of inositol depletion and the role of inositol depletion in bipolar disorder.  I believe that yeast is a powerful model in which to investigate this hypothesis, as much has been learned about the function of inositol and the regulation of its synthesis in yeast, mostly from Dr Henry’s studies.  Furthermore, the ‘awesome power of yeast genetics’ offers genetic approaches that are simply not feasible in complex eukaryotic models.  I decided to use yeast to elucidate the cellular consequences of inositol depleting drugs, and to test hypotheses generated by the yeast model in mammalian cells

Wenxi Yu: I obtained my BS in Biological Technology at Beijing Institute of Technology (China). I enjoy doing research and decided to pursue a scientific career. I was accepted by the graduate program of WSU and joined Miriam Greenberg’s lab. I am very interested in the anti-bipolar drug valproic acid (VPA), especially as it can alleviate both the manic and depressive symptoms of bipolar disorder. And although the drug has been prescribed for decades, the therapeutic mechanism is not understood. Dr Greenberg’s lab discovered cellular effects of VPA that are potentially related to the therapeutic effects of this drug. I hope my studies can help to identify the critical therapeutic effects of VPA and characterize the underlying therapeutic mechanisms.

Please could you give us an overview of your recent paper, ‘Inositol depletion, GSK3 inhibition and bipolar disorder’?

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