A Gut Feeling: Dr. Roger McIntyre’s 20-Year Journey of Research on GLP-1

The 2025 NEI Spring Congress began early on Wednesday, May 7, with a featured presentation by meeting chair Dr. Roger McIntyre, joined by Dr. Andrew Cutler. Together, they reflected on two decades of pioneering research into glucagon-like peptide-1 (GLP-1), offering insights into its evolving role in psychiatry.

Their discussion traced the progression of GLP-1 research from its origins in diabetes treatment to its implications for brain function. This work opened the door to exploring insulin’s involvement in psychiatric disorders such as depression and bipolar disorder. They focused on the emerging potential of GLP-1 receptor agonists—initially developed for diabetes and weight loss—as possible disease-modifying therapies for mental health conditions. These include not only relapse prevention in mood disorders but also the treatment of cognitive deficits associated with schizophrenia and Alzheimer’s disease.

Mental health conditions like depression and bipolar disorder frequently co-occur with metabolic issues such as obesity, type 2 diabetes, and metabolic syndrome. Patients with these comorbidities often exhibit more severe cognitive impairments—spanning executive function, memory, attention, and processing speed—many of which appear to worsen over time. These individuals also tend to show more pronounced anhedonia, especially in terms of motivation and reward processing.

While GLP-1 is well known for regulating insulin secretion in response to glucose, inhibiting glucagon, and influencing gut motility and satiety, it was later discovered that GLP-1 is also synthesized in the brain. It engages neural pathways in regions responsible for appetite (hypothalamus), cognition (hippocampus and cortex), and reward (ventral tegmental area). Postmortem studies have shown reduced expression of GLP-1 receptors in the hippocampus of individuals with major depressive and bipolar disorders.

Observational data further suggest that GLP-1-based treatments not only aid in weight loss and glucose control but may also slow cognitive decline in people with diabetes and potentially lower the risk of mild cognitive impairment (MCI) and Alzheimer’s disease. In animal models, GLP-1 agents like liraglutide have been shown to protect the brain against chronic stress and corticosteroid exposure, with evidence pointing to glutamate-mediated mechanisms of neuroprotection.

A central theme of Drs. McIntyre and Cutler’s presentation was the interplay between insulin, GLP-1, and glutamate—a triad with profound implications for psychiatric care. For instance, insulin can stimulate both GLP-1 and glutamate activity, while NMDA receptor antagonists like dextromethorphan (approved in combination with quinidine for depression) also enhance GLP-1 signaling.

The outlook for GLP-1 research is highly promising, particularly in its potential to reshape the treatment landscape for psychiatric and neurocognitive disorders through true disease modification.

The recording of this presentation, as well as all of the presentations from 2025 NEI Spring Congress, will be made available on the NEI website as Encore Presentations for NEI Members.

Source:
Roger S. McIntyre, MD, FRCPC and Andrew J. Cutler, MD. A Gut Feeling: Dr. Roger McIntyre’s 20-Year Journey of Research on GLP-1. Presented May 7 at 2025 NEI Spring Congress, Philadelphia, PA.