​ ​Dr. Rodrigo Mansur
"This study could help define completely new lines of treatment for depression," says Dr. Rodrigo Mansur, staff psychiatrist, Mood Disorders Psychopharmacology Unit at UHN. (Photo: UHN)

Researchers know that people with depression are two to three times more likely than the general population to suffer from Type 2 diabetes, the most common form of diabetes thought to be caused by a combination of genetics and lifestyle factors. They also know that half of all people diagnosed with depression are obese and at high risk of developing Type 2 diabetes.

But what they don't know is why there is this link between diabetes and depression.

Exactly what underlies the connection between these mental and physical illnesses is a question UHN psychiatrist Dr. Rodrigo Mansur hopes to better understand in a novel new study that could potentially change how we understand the biology of depression.

Instead of looking at the traditional molecules implicated in depression, such as serotonin, Dr. Mansur, who is based in the UHN Centre for Mental Health's Mood Disorders Psychopharmacology Unit (MDPU) at the Poul Hansen Centre for Depression, will explore the brain's sensitivity to insulin – the hormone that plays a key role in Type 2 diabetes – and the effect it has on patients with major depressive disorder (MDD).

A key trait of MDD is a markedly diminished interest in, or pleasure from, usual activities. This symptom – called anhedonia – is one of the most debilitating features of depression and linked to premature mortality. It is thought to be caused by a dysfunction to the brain's reward system, which governs our response to positive situations and stimuli.

Anhedonia is also a common symptom reported by people with metabolic conditions such as Type 2 diabetes.

"Traditional antidepressant medications are usually better for the more emotional aspects of depression, such as persistent sadness and negative thinking, than they are for symptoms like anhedonia," says Dr. Mansur.

"That gave me the motivation to try to understand what causes this symptom."

Study set to start later this year

Uncovering the relationship between insulin, anhedonia and depression could help us discover what underlies the co-occurrence of mood and metabolic disorders, which can help shed light on both these conditions.

The study – set to start later this year – will focus on the striatum, an area of the brain that's involved in the regulation of anhedonia. Dr. Mansur will investigate how people with MDD respond to insulin while completing a task designed to measure their willingness to exert greater effort to receive a larger reward.

The insulin will be administered by nasal spray, a recent approach that delivers the hormone directly to the brain.

"One of the novelties of this study is the methodology," says Dr. Mansur. "Most studies measure glucose in the blood to derive how sensitive the body is to insulin. But that doesn't tell us much about the brain because fundamentally the brain processes insulin differently."

To evaluate the response to insulin, the study will map the brain activity of study participants using functional magnetic resonance imaging (fMRI) while they complete an effort-based task and then compare that brain activity against a placebo group.

"Functional neuroimaging has been used in obesity and diabetes research to explore how the brain responds to insulin, but that has not yet been done in psychiatry," says Dr. Mansur. "We are trying to bring in these tools and frameworks to our practice to expand the knowledge we have on depression, such as a shared risk factor there that connects it with diabetes."

Dr. Mansur believes this is the first study to directly measure brain insulin sensitivity for mood disorders. It will be funded by a $570,000 grant he received from the Canadian Institute of Health Research (CIHR).

People with mental health issues have lower life expectancy

One of the key priorities of the UHN's Centre for Mental Health is researching the connection between mental and physical health.

Life expectancy for people with mental health issues is approximately 15 years lower than the general population. Though suicide is unfortunately common, the number one cause of death in this population is cardiovascular disease, which is the leading cause of death for people with diabetes.

"The mental health system does not pay as much attention as it should to the physical health of patients," says Dr Mansur. "Given this clear correlation, we need to do a better job of this in psychiatry."

This year marks the centenary of the discovery of insulin at the University of Toronto. An assistant professor at the same university, Dr. Mansur hopes to add to this long legacy of innovative research that improves the lives of patients.

"This study could help define completely new lines of treatment for depression, which is potentially very exciting," he says. "So instead of using medications that target serotonin, we can use medications that target the metabolic system, like medications that are used for diabetes, for example."

Dr. Mansur will begin recruiting patients for the brain insulin clinical study later this year, with final results expected in 2026.

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