Mental illness is the leading cause of disability in Canada – in any given year, 1 in 5 people experience mental health problems or addiction. Major depressive disorder, along with other mood disorders such as bipolar disorder, is among the most common types of mental illnesses and, while treatments are available, most have moderate success.

An initial course of antidepressants, for example, will only be effective for about a third of people, and can often have non-negligible side effects which may discourage patients from taking them. Over the last two decades, scientists have been exploring an alternative to antidepressants called transcranial magnetic stimulation (TMS), a non-invasive procedure that uses magnetic fields to manipulate brain activity. Neural plasticity, the brain’s ability to modify neural networks in response to internal or external stimuli, is impaired in major depressive disorder and TMS, which enhances neural plasticity, can therefore help alleviate some symptoms of depression.

“The hope is that we discover a more effective and more potent treatment for people with depression … and also reduces the risk of developing dementia that is linked to depression.” – Tarek Rajji

More recently, a new type of TMS protocol known as theta-burst stimulation (TBS) has been developed, which has reduced treatment time from about 40 minutes down to 3 minutes, making the treatment very tolerable for patients. Unfortunately, despite having fewer side effects than medication, TBS is not much more effective – it helps alleviate depression symptoms in roughly 40% of patients.

A new study funded through the Bell Let’s Talk – Brain Canada Mental Health Research Program led by Dr. Tarek Rajji and conducted at the Centre for Addiction and Mental Health, Mt Sinai Hospital, and the University of Toronto is aiming to change that. “The hope is that we discover a more effective and more potent treatment for people with depression that not only treats depression but also reduces the risk of developing dementia that is linked to depression,” said Dr. Rajji.

TMS protocols were based on stimulation protocols discovered and refined in rodents, in a brain structure called the hippocampus. However, since the hippocampus lies deep in the brain, treatment in humans is done on the prefrontal cortex, a part of the brain with very different structure and function. As such, the first step will be to investigate how TBS works in the murine equivalent of the prefrontal cortex using brain slices. This work, led by Dr. Graham Collingridge at Mt Sinai Hospital and Dr. Evelyn Lambe at Temerty Faculty of Medicine at University of Toronto, will also test a new protocol in these slices that uses a longer interval between the periods of stimulation, since preliminary research has demonstrated that this has a more lasting impact on neural plasticity.

Once they have optimized their new protocol, the team will then use live mice to test it and determine the stability of the induced changes in neural plasticity. To maximize the applicability of their work to humans and to further adapt their protocols, the team will also use “depressed” mice for these experiments, with depression-like behaviours arising from gene variants or changes in their environment. Together, the data generated from these mouse studies will provide critical information to the research team as they tackle the final phase of their project: testing their new TBS protocol on depressed patients. Based on their current knowledge, the team expects that the new approach will induce higher and more sustained neural plasticity in depressed patients.

This is an innovative “Bench to First-in-Human” approach, taking study from brain slices, to live animals, to humans. As such, it is important to make sure that the protocol responds to the actual needs of the community. To this end, Dr. Rajji and a research team led by Dr. Sanjeev Sockalingam will engage with knowledge users such as scientists, trainees, patients and families and representatives from relevant provincial and national organizations throughout the project.

As Dr. Rajji says, “the very exciting part […] is the focus on translational research that’s bringing together basic scientists with clinical researchers and experts in knowledge translation in order to optimize an exciting novel treatment for depression.” Encouraging the involvement of subject matter experts from the earliest stages of the project will ensure that the outcomes of the project truly help the patients and that there will be uptake among clinicians, hopefully leading to a much-needed improvement in how depression is treated in the near future.

To learn more about Brain Canada funded research, please visit www.braincanada.ca