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Uncovering bipolar disorder’s molecular map

Posted: 10th June 2021

The world's first treatment for bipolar disorder was discovered in the 1940s by a psychiatrist-researcher working in an abandoned pantry in the Bundoora Repatriation Mental Hospital in Melbourne’s north. Now, 70 years later, a fellow Melburnian is forging a path to potential new bipolar treatments. 

“Dr John Cade’s use of lithium – a potentially toxic substance – to treat patients with bipolar was an early medical research breakthrough,” says Dr John Scott, Head of SVI’s Neurometabolism Laboratory. “Cade was so dedicated to helping his patients that he experimented with lithium on himself to establish a safe dose. But he was never able to pinpoint exactly how, or why lithium worked.” 

That mystery still remains today, and lithium is still the sole front-line treatment for people living with bipolar disorder. 

Cue John Scott, who is laying new groundwork in understanding how and why bipolar disorder develops – essential knowledge in the search for new treatment options for a disease affecting 1 in 50 Australian adults each year. 

“It is now becoming clear that the manic and depressive phases of bipolar disorder are triggered by imbalances in brain energy metabolism,” John explains. “My work focuses on an enzyme called Ca2+-calmodulin dependent protein kinase kinase-2, or more simply, CaMKK2, which regulates energy balance.” 

Studies undertaken by John and his team have shown that mutations in humans which stop the normal function of CaMKK2 are associated with bipolar disorder. He’s also gone some way to establishing that the effectiveness of lithium is likely a happy accident related to it acting on the same energy pathway – lending additional evidence that CaMKK2 might prove a good target for developing new, less toxic treatments. 

“Fundamental research of this kind is critical,” says Deakin University’s Professor Michael Berk, a clinical psychiatrist and researcher, one of John’s collaborators. 

“Unless we can understand the molecular basis of the ‘toggle switch’ between mania and depression in bipolar disorder, we will continue to be unable to design targeted therapies. Instead, we rely on serendipity to treat this devastating disease.” 

By investigating mice as a model for how brain energy regulators work in humans, John and his team are uncovering bipolar disorder’s molecular map. They have also generated small molecules – potential drugs – that affect CaMKK2 function. 

“It’s been a long time coming, but I’m optimistic that we are getting closer to creating more effective treatments for bipolar and other mental health disorders,” says John. 

Future treatments flowing from this leading-edge research will be due to the collective effort of scientists and clinicians – dating back to trailblazers like John Cade – in unravelling the complex biological mechanisms deep inside our brains. 

For more information please see: Neurometabolism