By Karen Fang

Graphic design by Athena Li

Mood disorders, such as major depressive disorder (MDD) and bipolar disorder (BD), are mental health conditions that affect emotional states and impact up to 15% of the Canadian population.¹ Historically, mood disorders have been examined through the lens of imbalance in neurotransmitters like serotonin. Despite a heavy focus on the neurological underpinnings of these conditions, patients with mood disorders often have physical comorbidities. Rather unexpectedly, the leading cause of death in patients with mood disorders is not suicide, but cardiovascular disease.² This reality has shifted the focus of recent investigations toward the mechanisms that link the mind and the body.

Dr. Rodrigo Mansur is a staff psychiatrist at the Toronto Western Hospital and an Associate Professor in the Department of Psychiatry, Division of Neurosciences and Clinical Translation at the University of Toronto. Dr. Mansur completed his medical training at the Universidade Federal de São Paulo/Escola Paulista de Medicina (UNIFESP/EPM) in Brazil. He completed his psychiatry residency training and PhD at UNIFESP/EPM and then went on to do his fellowship training in psychiatry at the University of Toronto.

With extensive clinical experience in mood disorders, Dr. Mansur notes that his interest in metabolic dysfunction arose from the observation that patients with mood disorders are two to three times more likely to develop diabetes.³ This may be due to lifestyle factors, like smoking or poor dietary habits, or treatment-related factors, as certain medications may lead to weight gain.³ However, these factors alone do not fully explain the increased risk of metabolic disease in these patients. “Patients with mood disorders often show indicators of metabolic disease, such as insulin resistance, that precede any diagnosis of mental health disorders,” Dr. Mansur explains. This indicates that there may be a connection between mental health disorders and metabolic disease, which has become a central focus of his research in recent years.

One major area of Dr. Mansur’s research is brain insulin signalling in patients with BD. While impaired insulin signalling, or insulin resistance, is typically studied in organs like the liver and skeletal muscle in the context of diabetes or obesity, the brain also widely expresses insulin receptors. For example, insulin receptors are expressed in the hippocampus, which is involved in memory formation, and the ventromedial prefrontal cortex (vmPFC), which is linked to decision making and cognitive function. In the brain, insulin signalling has been implicated in neuroplasticity and cognitive function.⁴ Recent research has shown that patients with BD are more likely to be insulin resistant, suggesting a potential role for disrupted insulin signalling in the pathophysiology of BD.⁵ However, unlike other organs in the body, brain signalling pathways cannot be evaluated by blood tests, highlighting a major challenge in neuropsychiatric research. 

To overcome this, Dr. Mansur’s team evaluated the brain-insulin pathway using an innovative approach: neuronal extracellular vesicles (NEVs) from blood samples.⁶ NEVs are membrane vesicles originating from neurons, which allows the team to study signalling pathways without the need for invasive procedures.⁶ Blood samples were obtained from patients with BD enrolled in a clinical trial evaluating the effect of infliximab, a drug known to promote insulin sensitivity. At baseline, NEV biomarkers of insulin resistance were associated with cognitive dysfunction and reduced vmPFC volume as measured by magnetic resonance imaging (MRI). Treatment with infliximab led to increased activity in insulin signalling and increased brain volume.⁶ These results suggest that impaired insulin signalling may contribute to cognitive dysfunction and structural brain changes that are typical of BD. This study is the first to evaluate insulin signalling in the brain and points to the therapeutic potential of modulating insulin sensitivity for patients with BD.

Building on the importance of metabolic pathways in mood disorders, Dr. Mansur’s team has recently turned their attention to the use of metabolic agents for the treatment of MDD. Specifically, the team focused on glucagon-like peptide 1 receptor agonists (GLP-1 RAs), a class of drugs originally designed for diabetes and obesity. Recent research has also linked GLP-1RAs to other clinical effects, including reduced cardiovascular events, improved kidney and liver function, and improved cognitive function.^7,8 

In a 2026 study, Dr. Mansur’s team evaluated the safety and efficacy of the GLP-1 RA semaglutide for the treatment of cognitive dysfunction in adults with MDD in a clinical trial.⁹ In this randomized, double-blind trial, 72 adults with MDD and obesity/overweight, who showed cognitive impairment, were given 14mg of oral semaglutide or a placebo control over 16 weeks. Cognitive function was assessed using a range of neuropsychological tools and questionnaires. Semaglutide did not improve executive function, which includes complex processes like problem-solving and reasoning. However, it did demonstrate beneficial effects on global cognition, which includes memory and attention. Furthermore, semaglutide reduced body weight without affecting depressive symptom severity or suicidal ideation.⁹ This study is the first to demonstrate the safety of semaglutide for patients with MDD and the potential efficacy of semaglutide for specific cognitive domains. Together, these results underscore the role of metabolism in mood disorders and provide a rationale for further investigations into brain metabolic pathways and repurposing of metabolic agents for psychiatric disorders. 

The intersection of metabolic and psychiatric disorders is an evolving field that demands a whole-body perspective. “Conventionally, psychiatric disorders are often treated separately from the rest of the body, but there is an intrinsic connection between physical and mental health,” Dr. Mansur says. To adapt to the heterogeneous nature of psychiatric disorders, researchers and clinicians are moving away from a one-size-fits-all treatment approach. Dr. Mansur emphasizes the need for more mechanistic studies to disentangle the complex brain metabolic pathways and importantly, larger randomized controlled trials to evaluate potential therapeutic interventions for patients with psychiatric disorders. Overall, Dr. Mansur’s research provides direct evidence supporting the role of metabolism in mood disorders and compels us to consider more integrated approaches to psychiatric treatment that extend beyond neurological modulation.  

References

1. Statistics Canada. Table 13-10-0465-01 Mental health indicators 2023.
2. Walker ER, McGee RE, Druss BG. Mortality in Mental Disorders and Global Disease Burden Implications. JAMA Psychiatry 2015;72:334.
3. Possidente C, Fanelli G, Serretti A, et al. Clinical insights into the cross-link between mood disorders and type 2 diabetes: A review of longitudinal studies and Mendelian randomisation analyses. Neurosci Biobehav Rev 2023;152:105298.
4. Kleinridders A, Ferris HA, Cai W, et al. Insulin action in brain regulates systemic metabolism and brain function. Diabetes 2014;63:2232–43. 
5. Coello K, Vinberg M, Knop FK, et al. Metabolic profile in patients with newly diagnosed bipolar disorder and their unaffected first-degree relatives. Int J Bipolar Disord 2019;7:8.
6. Mansur RB, Delgado-Peraza F, Subramaniapillai M, et al. Exploring brain insulin resistance in adults with bipolar depression using extracellular vesicles of neuronal origin. J Psychiatr Res 2021;133:82–92.
7. Badve S V, Bilal A, Lee MMY, et al. Effects of GLP-1 receptor agonists on kidney and cardiovascular disease outcomes: a meta-analysis of randomised controlled trials. Lancet Diabetes Endocrinol 2025;13:15–28.
8. Ballum H, Dri C, Liao S, et al. The effect of glucagon-like peptide 1 (GLP-1) receptor agonists on cognition: A systematic review of systematic reviews and meta-analyses. J Affect Disord 2026;402:121310. 
9. Badulescu S, Gill H, Shah H, et al. Semaglutide for the treatment of cognitive dysfunction in major depressive disorder: A randomized clinical trial. Med 2026;7:100916.