Expert Calls for Research into GLP-1s for Mental Illness

MILAN — Recent research allaying concerns about suicidality linked to glucagon-like peptide 1 (GLP-1) receptor agonists, along with evidence of these agents’ potential psychiatric and cognitive benefits, has prompted the lead investigator of a major analysis to urge researchers to explore the potential of these drugs for mental illness.

“So far, we’ve been talking about the safety from a neuropsychiatric perspective in diabetes, but there is also the safety and benefit in people with mental disorders,” Riccardo De Giorgi, MD, PhD, from the Department of Psychiatry, University of Oxford, Oxford, England, told Medscape Medical News.

The results of the meta-analysis were previously reported by Medscape Medical Newsand reviewed by De Giorgi at the 37th European College of Neuropsychopharmacology (ECNP) Congress. De Giorgi broached whether GLP-1 inhibitors such as semaglutide might also offer the same benefits in patients without diabetes as they do in those with diabetes, in terms of cognitive deficits and substance use or mood disorders.

Noting that GLP-1s are not approved for psychiatric disorders, De Giorgi said it can’t be assumed that the “metabolic or maybe even more general mechanisms that are being modified with these medications in diabetes or even in obesity are the same for people with psychiatric disorders. We’re talking about very different things. From a clinical perspective, you could do real harm,” he told Medscape Medical News.

Yet De Giorgi emphasized the importance of exploring the potential benefits of these medications in psychiatry.

“From a research perspective…I am very worried about missing an opportunity here. This happened with rimonabant, a cannabis medication that was used for weight loss back in 2012 and was withdrawn quite dramatically in Europe immediately after licensing because it increased suicide risk. Since then, nobody has been touching the cannabinoid system, and that’s a shame because in psychiatry, we don’t have that much we can work on. So we don’t want to miss an opportunity with the GLP-1 system — that’s why we need to be cautious and look at safety first,” he said.

Signal of Efficacy?

De Giorgi’s research suggested several potential neurobiological effects of GLP-1 inhibition in diabetes research.

“There was a bit of a signal specifically for the big three dementias — vascular, Lewy Body, and frontotemporal — although there was not enough power,” he reported. “We also saw a reduced risk in nicotine misuse, especially amongst other substance use disorders…and finally a more tentative association for reduced depression,” he added.

He noted that GLP-1s for psychiatric illness likely have limitations and may not cure mental disorders but could help specific subsets of patients. He pointed out that rather than aiming for large-scale studies, the focus should be on small, incremental studies to advance the research.

Asked by the session chair, John Cryan, PhD, from University College Cork, Cork, Ireland, and chair of the ECNP Scientific Committee whether improvement in patients’ mood could be attributed to weight loss, De Giorgi replied no.

“We now have quite a lot of studies that show that if there is an effect or association it is seen quite a bit earlier than any weight loss. Remember, weight loss takes quite a lot of time, and at quite high doses, but more provocatively, even if that’s the case, does it matter? We as psychiatrists do worry that we need to disentangle these things, but they don’t do that in cardiology, for example. If they see a benefit in mortality they don’t really care if it’s specifically an effect on heart failure or ischemic disease,” said De Giorgi.

Regardless of their neuropsychiatric potential, the cardiometabolic benefits of GLP-1 inhibitors are sorely needed in the psychiatric population, noted two experts in a recent JAMA Psychiatry viewpoint article.

Sri Mahavir Agarwal, MD, PhD, and Margaret Hahn, MD, PhD, from the University of Toronto and the Schizophrenia Division at the Centre for Addiction and Mental Health, in Toronto, Ontario, Canada, pointed out in a recent editorial published in JAMA Psychiatry that “individuals with severe mental illness (SMI) have exceedingly high rates of metabolic comorbidity; three of four are overweight or obese, whereas the prevalence of type 2 diabetes (T2D) is several-fold higher than in the general population. Consequently, individuals with SMI die 15-20 years earlier from cardiovascular disease (CVD) than do those in the general population with CVD,” they noted.

“The arrival of semaglutide has infused significant enthusiasm in the field of mental health research. The proximal effects of weight and related CV comorbidities are significant in themselves. It is plausible that semaglutide could act through neurogenesis or secondary benefits of improving metabolic health on other important outcomes, such as cognitive health and quality of life, thereby filling an unmet need in the treatment of SMI,” Agarwal and Hahn added.

An Exciting Opportunity

Current research investigating GLP-1s in psychiatry and neurology is increasingly focused on neuroinflammation, said De Giorgi.

Research shows significant evidence that certain medications may help reduce dysfunctional inflammatory processes linked to various cognitive and psychiatric disorders, he added.

Many patients with established psychiatric conditions also have physical health issues, which contribute to increased mortality risk, said De Giorgi. It’s crucial to understand that if these treatments improve mortality outcomes for psychiatric patients, the specific mechanisms involved are secondary to the results. Psychiatrists must be equipped to prescribe, manage, and initiate these therapies, he added.

“While trials involving psychosis patients are ongoing, we are making progress and should seize this opportunity” said DiGiorgi.

Cryan agreed: “I think we’ll get there. What these drugs have shown is that you can, through a single mechanism, have multitude effects related to brain-body interactions, and why not focus that on mood and anxiety and cognitive performance? It’s exciting no matter what. We now need to do longitudinal, cross-sectional, placebo-controlled trials in specific patient populations,” Cyran said.

This study received funding from the National Institute for Health and Care Research Oxford Health Biomedical Research Centre and Medical Research Council. De Giorgi’s co-authors reported receiving funding for other work from Novo Nordisk, Five Lives SAS, Cognetivity Ltd., Cognex Ltd., P1vital, Lundbeck, Servier, UCB, Zogenix, J&J, and Syndesi. Cryan reported no relevant disclosures.