Designing a Semaglutide Study in Psychiatry, with Roger S. McIntyre, MD

Though its clinical benefit for cardiometabolic, renal, hepatic, and obesity medicine may seem too good to be true, the incretin therapy drug classes of GLP-1 and GIP receptor agonists are proving to be an increasingly realistic pathway-targeting agent for a litany of chronic diseases.

Even for indications like psychiatric disease, drugs like semaglutide (Ozempic) may be something more certain than a pipe dream.

In the second segment of an interview with HCPLive during the American Psychiatric Association (APA) 2024 Annual Meeting, Roger S. McIntyre, MD, professor of psychiatry and pharmacology at the University of Toronto, discussed the tangible prospects of treating psychiatric disease with GLP-1 and GIP receptor agonists. He explained the rationale starts with understanding the “disproportionate” expense of energy from the brain—despite representing about 5% of a person’s bodyweight, the brain consumes about 25% of all the body’s energy.

“So, it's very susceptible to things like oxidative stress,” McIntyre said. “And in addition to being anti-inflammatory, in addition to being neuroprotective, GLP-1s are shown to be antioxidant. And the antioxidant capacity of these agents is, of course, ringing therapeutic bells—maybe there's something of an opportunity, but we are also scratching our head saying, 'Is it the case this is all association? Is it possible that changes in GLP-1 signaling...are they causing mental illness?’”

There’s at least some evidence to support that hypothesis, McIntyre said. For one, increasing data show that patients receiving GLP-1 agonists for conditions like diabetes are at a significantly lowered risk of depression and cognitive issues.

“So, in other words, that gives us reason to believe that they're preventative—but also indirectly is validating a hypothesis that maybe GLP-1 dysregulation is not just associated, maybe it's causative,” McIntyre explained. “ Because we know that mental disorders are heterogeneous from a causal and pathologic perspective; maybe this is one of the suspects in the causal category.”

When asked to prospect what exactly a late-stage clinical trial assessing a drug like semaglutide for a condition like depressive disorder or alcohol use disorder would like, McIntyre said it would likely include standard outcomes including patient-reported disease severity and measures of behavior (i.e., heavy drinking days, etc). However, a more “conceptually supported and mechanistically informed” trial may consider the opportunity to prevent worsening psychiatric health: can a GLP-1 agonist slow disease progression in an early-stage patient?

“For example, let's say you're somebody who's getting a little older and you start having mild cognitive impairment. If you took one of these agents, could that slow down the progression of Alzheimer's disease?” McIntyre said. “That would be interesting. Secondly, if you are someone who has, let's say, depression or bipolar disorder, and you take one of these agents over the next 6 months, 12 months, 18 months, are you less likely to have a recurrence of the illness?”

McIntyre advised his peers consider 2 paradigms of treatment outcomes in such studies: the acute symptom-mitigative effects of the drug class, and the opportunity to prevent progressive disease.

“Taken together, the science around GLP-1 and GIP (agonists) to some extent gives reason to believe that they are shaping the arc—the trajectory of domains of psychopathology like cognitive impairment, reward disturbance and motivation,” he said. “So I would see it as…an acute treatment paradigm. Look at people with alcohol use disorder—do they reduce alcohol consumption? That's certainly a very valid paradigm. But I would be especially interested in looking at changing the trajectory of cognitive impairment and those at risk, maybe changing the trajectory of recurrence vulnerability of those at risk across time.”