Research provides tremendous hope for 1.6M Canadians living with bipolar disorder

Brain Canada/Bell Let’s Talk study aims to fast-track diagnosis and treatment, delve into the underlying causes, and identify new drug targets

A Canadian research team, based in Montreal and Halifax, is using sophisticated stem cell technology to uncover the causes of bipolar disorder, develop new ways to screen for it, determine who will respond to treatment, and begin to identify new drug therapies.

Funded by Brain Canada/Bell Let’s Talk, the research could have a profound impact on the lives of four per cent of Canadians, or 1.6 million people, who live with the debilitating condition.

“Bipolar disorder is quite common, and it’s a big issue in our society,” says one of the project leaders Dr. Austen Milnerwood, a neurophysiologist, Killam Scholar, and Associate Professor in the Department of Neurology & Neurosurgery at McGill University’s Montreal Neurological Institute (‘The Neuro’).

Characterized by severe mood swings – from deep depression to mania – bipolar disorder, or BD, impacts all aspects of life. Most worrisome, about 30 per cent of people with the condition attempt suicide, and about 15 per cent of those attempts are completed.

One of the biggest challenges with BD is that it’s commonly misdiagnosed and treated as depression, causing lost time and misery for those affected. And, while the gold-standard treatment for BD is lithium, fewer than a third of people respond to the drug. “In that 30 per cent, it works incredibly well, but for the majority, up to 70 per cent, it doesn’t have a very useful effect at all,” Dr. Milnerwood says.  Even in people who respond to lithium, the drug has drawbacks. Close monitoring of patients is needed, and prolonged use can lead to health consequences, including kidney damage.

That’s why the Brain Canada/Bell Let’s Talk study, which began in 2022, is so incredibly important to individuals and families living with this illness. The research aims to identify a biomarker (a molecule found in blood or other biofluids) that would fast-track diagnosis and treatment, delve into the underlying causes of disease, and provide new or repurposed medications to treat it.

What we really want to do is work out what causes bipolar disorder, find out how lithium works for people who respond to it, and see if we can leverage that insight to treat bipolar patients who don’t respond to lithium, in case there’s a similar mechanism at play. We also want to try to replace the lithium itself with something that is a little bit easier to manage.

Dr. Milnerwood

The A-team of clinical and research leaders is overseeing this Canadian effort, including psychiatrist Dr. Martin Alda, one of the world’s foremost authorities on BD and lithium response. Dr. Alda, Professor and Killam Chair in the Department of Psychiatry at Dalhousie University, collected blood samples from patient donors and provided clinical data. “We couldn’t have done any of this without his expertise and his guidance,” Dr. Milnerwood says.

Samples were sent to the team of scientists in Montreal, led by Dr. Milnerwood and prominent geneticist and neurologist Dr. Guy Rouleau, Director of The Neuro and Chair of Neurology and Neurosurgery at McGill. Dr. Anouar Khayachi and colleagues reprogrammed white blood cells to behave like stem cells (the body’s master cells), and then morphed them into nerve cells (neurons) to observe how they form neural networks and communicate. Fifteen years ago, this technology would have been unimaginable.

So far, the research team has created cell lines (cultures of cells) from 15 people who fall into three categories: BD lithium responders, people with BD who don’t respond to lithium, and matched controls. From there, researchers are comparing network function, genes and proteins to tease out the differences.

The research has produced some fascinating insights:

• Neurons derived from people with bipolar disorder demonstrate a high level of excitability compared to cells from healthy persons;
• Treating neurons with lithium quietens down hyperactivity in the cells of lithium responders, but not in cells of non-responders. In other words, it’s possible to identify who will respond to lithium by measuring electric activity in their cells;
• The underlying changes in BD neurons, and those modified by lithium in responders, highlighted processes that regulate cell metabolism. Targeting these processes with other drugs quietened down hyperactivity in neurons from BD lithium responders and, importantly, also those from people who did not. This means that a potential new treatment avenue for BD was found.
• People with bipolar disorder are much more likely to have metabolic issues like insulin resistance and Type-2 diabetes. And, according to research by the Halifax group, individuals treated with the diabetes drug metformin appear to see improvements in their psychiatric symptoms. The cause-and-effect for the link between metabolic processes – the enzymes that control cell metabolism – and what’s happening in the brain requires further research.

As bipolar disorder itself, it’s interesting to note that lithium response also runs in families – so if one family member responds to the drug, it will likely have a good effect on others with the disorder.But “different forms of bipolar disorder respond to different so-called mood stabilizers,” Dr. Alda notes.

As the Brain Canada/Bell Let’s Talk project wraps up in 2025, researchers look for further funding to create more cell lines (each one costs about $45,000 to develop and initially maintain) in order to build on and validate their findings, and continue meaningful progress towards the development of optimal treatments for an illness that impacts so many Canadians and their families.