BBDC Member Profile

Mahavir Agarwal, MBBS, MD, PhD

June 2023
By Krista Lamb

The connection between diabetes and mental health has long been appreciated, though the precise nature of how these conditions are linked is still unclear. For psychiatrist and scientist, Dr. Mahavir Agarwal, who in 2022 received a Novo-Nordisk-BBDC New Investigator Award, this intersection is one he hopes to better understand.

After medical school and specialized training in India, Dr. Agarwal moved to Canada for a research fellowship with Dr. Maggie Hahn at the University of Toronto in the Department of Psychiatry. Here, he examined the impacts of schizophrenia that overlap with metabolic abnormalities such as type 2 diabetes using neuroimaging techniques in hopes of better understanding these two diseases. Now a clinician-scientist in the Schizophrenia division at the Centre for Addiction and Mental Health (CAMH) and an Assistant Professor at the University of Toronto, he will further investigate the link between type 2 diabetes and mental health.

Working as a psychiatrist, Dr. Agarwal noticed a significant overlap between type 2 diabetes and depression.  “A lot of the severe mental illnesses that I trained in have very high rates of metabolic dysfunction, including diabetes, obesity and dyslipidemia. And some of the drugs that we use, especially antipsychotics, add to that problem. Initially, I started from that point of view, looking at how to improve the physical health of those who are afflicted with mental health challenges. It seemed to me that this was a sort of a double whammy for them. Not only do they have to deal with the mental health challenges, but also the physical health effects,” he says.

Dr. Agarwal was particularly interested in how type 2 diabetes impacted those with schizophrenia. The development of antipsychotics led to improvements in how the condition was managed, but the side effects of these therapies have continued to be an issue. One of the major side effects of current treatments is weight gain, which can increase the risk for type 2 diabetes. “Our patients are significantly more likely to be obese and develop type 2 diabetes compared to the general population, and there are a lot of problems because of that,” he explains, noting that people with schizophrenia tend to have shorter lifespans than those without – often by 15 to 20 years – and that this is driven by poor cardiovascular health, rather than the psychiatric condition.

Determining the underlying pathophysiology of the link between type 2 diabetes and depression or schizophrenia felt like an important next step in developing potential therapies. Dr. Agarwal decided to focus on insulin action in the brain, as an important contributor to how these conditions can interact. As a researcher who had only worked with humans, the pandemic gave him the time and opportunity to work with rodent models. He and Dr. Hahn collaborated on a series of experiments using rodents to investigate the links. They knew that antipsychotics caused metabolic abnormalities and hypothesized that this was in part via blocking insulin action in the brain. They were intrigued to see that these therapies caused deleterious effects from the very first dose. “This means that you don’t need to have weight gain to have diabetes-related changes,” Dr. Agarwal explains. “Our rodent work has shown that even acute dosing of antipsychotics can interfere with insulin action in the brain.”

He is currently investigating whether this can be recapitulated in humans; and, if so, what changes to care could improve metabolic outcomes for people living with diabetes and schizophrenia or depression. Dr. Agarwal has also initiated clinical trials to examine at the efficacy of diabetes drugs, such as metformin or newer therapeutics such as semaglutide, and how combining these drugs with antipsychotic agents could be effective in improving metabolic and/or psychiatric parameters.

Continuing both lines of work, Dr. Agarwal sees many more ways that basic and clinical research can be combined to provide greater understanding of the metabolic implications of mental health. As a clinician, the impact this could have on his patients is a continual inspiration for his research. He also knows that greater understanding of these conditions could also apply to those with diabetes without mental health conditions, “If we were to find that brain insulin resistance underlies the overlap between depression and diabetes, that gives you an avenue for intervention in the diabetes field as well,” he says. This would be one side effect he’d find very gratifying.