Roger S. McIntyre, MD: GLP-1 Agonists for Psychiatry?

GLP-1 / GIP receptor agonists including semaglutide (Ozempic) and investigative retatrutide are representative of a seismic shift in cardiometabolic and comorbidity treatment. Over the last decade, the emerging drug class has been robustly evidenced to effectively treat type 2 diabetes, as well as persistent comorbidities including cardiovascular events, chronic kidney disease, fatty liver disease and clinical obesity—among other outcomes.

To perhaps little surprise, they may have a role to play in psychiatric treatment.

In an interview with HCPLive during the American Psychiatric Association (APA) 2024 Annual Meeting in New York, NY, this week, Roger S. McIntyre, MD, professor of psychiatry and pharmacology at the University of Toronto, discussed his presentation topic evaluating the prospect of GLP-1 receptor agonists in the treatment of psychiatric disorders.

As McIntyre explained, the potential benefit with the dynamic drug class would be three-fold.

“We now have reasons to believe that mechanistic steps that lead to symptom relief in many mental disorders includes activating molecular and cellular systems in the brain relevant to neuroplasticity, neuroprotection, and so-called anti-apoptosis—keeping cells alive. This is a mechanism shared by antidepressants, shared by neurostimulation—like transcranial magnetic stimulation—as well as by psychotherapy,” McIntyre said. “What's interesting about GLPs and GIPs, is similar to what I just described, they also activate molecular and cellular systems relevant to neuroplasticity, neuroprotection, anti-apoptosis.”

GLP-1 and GIP receptor agonists may provide some targeted, preventive effects in psychiatry akin to their effect in various chronic conditions, McIntyre said. The potential would be to address patient’s conditions with “mechanistically informed” therapy.

“We would prefer treatments that are able to target key mechanisms that are responsible for these syndromes that we have in the DSM,” he said. “We also would like to have treatments that are not simply suppressing symptoms, but hopefully are modifying the disease. It may be modifying the illness trajectory.”

McIntyre identified neurocognitive disorders including Parkinson and Alzheimer disease as viable clinical targets for the drug class; in the former condition, investigators have found evidence suggesting it may “slow down some of the progression of the motor problems so cardinal to that illness.” He additionally believes there may be opportunity to treat conditions including alcohol use disorder, among other substance issues.

“The prevailing view in obesity research today is that a key mechanism mediating the decrease in food consumption with obesity is modulating what we call reward salience. There's too much exaggerated reward for a cue in the environment,” McIntyre said. “So, people are looking at this very opportunity being GLP-1s to treat these types of other addictive disorders.”

Other opportune conditions for GLP-1 / GIP receptor agonists may include traumatic brain injury, stroke-related illness and depressive disorders, McIntyre said.

Lastly, McIntyre discussed the well-regarded clinical efficacy of the drug class on weight loss—an outcome that may be particularly promising to resolve the common antipsychotic treatment effect of uncontrolled weight gain.

“And we now have the beginning of an evidence base showing that GLP-1s could be extremely effective in helping not only weight gain that's been imparted by the underlying drugs, but also weight gain as part of the illness—helping not just weight but helping metabolic (conditions) and also helping blood pressure,” McIntyre said.

^{McIntyre has received research grant support from CIHR/GACD/National Natural Science Foundation of China (NSFC) and the Milken Institute; speaker/consultation fees from Lundbeck, Janssen, All Neumora Therapeutics, Boehringer Ingelheim, Sage, Biogen, Mitsubishi Tanabe, Purdue, Pfizer, Otsuka, Takeda, Neurocrine, Neurawell, Sunovion, Bausch Health, Axsome, Novo Nordisk, Kris, Sanofi, Eisai, Intra-C NewBridge Pharmaceuticals, Viatris, Abbie and Atai Life Sciences.}