Experts call for research into GLP-1 for psychiatric disorders

MILAN — Following recent studies easing concerns about suicidality associated with glucagon-like peptide 1 (GLP-1) receptor agonists and evidence of potential psychological and cognitive benefits of these drugs, the lead investigator of a large analysis has urged researchers to investigate the potential of these drugs for psychiatric disorders.

“So far we've talked about safety from a neuropsychiatric perspective in diabetes, but there is also safety and benefit for people with psychiatric illness,” said Riccardo de Giorgi, MD, PhD, of the department of psychiatry at the University of Oxford in the UK. Medscape Medical News.

The results of the meta-analysis Previously reported by Medscape Medical NewsReviewed by De Giorgi 37th Congress of the European College of Neuropsychopharmacology (ECNP)De Giorgi addressed whether GLP-1 inhibitors such as semaglutide might benefit non-diabetic patients as well as diabetics in terms of cognitive impairment, medication use and mood disorders.

Noting that GLP-1 has not been approved for psychiatric disorders, De Giorgi said: “It is unlikely that the metabolism, and perhaps more general mechanisms, that are altered by these drugs in diabetes and obesity are the same in people with psychiatric disorders. We are talking about something completely different. From a clinical perspective, there is the potential for real harm.” Medscape Medical News.

But De Giorgi stressed the importance of exploring the potential benefits of these drugs in psychiatry.

“From a research perspective… I am very concerned about a missed opportunity here. This is what happened with rimonabant, a cannabis drug used for weight loss in 2012. It was withdrawn quite dramatically. “In Europe, shortly after approval, the increased suicide risk meant that no one was touching cannabinoids, which is unfortunate because there isn't much left to do in psychiatry. We don't want to miss the chance with GLP-1, so we need to be cautious and think about safety first,” he said.

A signal of validity?

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

“There was some small but underpowered signal for the three major dementias in particular – vascular dementia, dementia with Lewy bodies, and frontotemporal dementia,” he reported. “We also saw a reduction in the risk of nicotine abuse, particularly in other substance use disorders. And finally, the association with reduced depression was more uncertain,” he added.

He pointed out that GLP-1 for psychiatric disorders has limitations and may not be able to cure psychiatric disorders, but it may be useful for certain patient groups. He pointed out that instead of aiming for large-scale studies, the focus should be on small, incremental studies to advance research.

Asked by session chair Dr John Cryan, chairman of the ECNP Scientific Committee at University College Cork in Ireland, whether the improvement in patients' mood was due to weight loss, De Giorgi said it was not.

“There's now quite a bit of research showing that if there's an effect or an association, it's going to happen much sooner than weight loss, which remembers that weight loss takes quite a long time and requires quite a bit of effort. But the more provocative question is, even if it does, does it matter? As psychiatrists, we worry about having to disentangle these things, but we don't do that in cardiology, for example. If we know there's a mortality benefit, we don't really care whether it specifically impacts heart failure or ischemic disease,” De Giorgi said.

Regardless of the neuropsychiatric potential, the cardiometabolic benefits of GLP-1 inhibitors are much needed for patients with psychiatric disorders, two experts noted. Recent JAMA Psychiatry Viewpoint Articles.

Sri Mahavir Agarwal, MD, and Margaret Hahn, MD, of the Schizophrenia Division at the University of Toronto and the Centre for Addiction and Mental Health, Toronto, Ontario, Canada Recent editorials Publication year JAMA Psychiatry “Patients with severe mental illness (SMI) have disproportionately high rates of metabolic complications, three in four are overweight or obese, and the prevalence of type 2 diabetes mellitus (T2D) is several times higher than in the general population. As a result, patients with SMI die from cardiovascular disease (CVD) 15 to 20 years earlier than patients with CVD in the general population,” the researchers noted.

“The arrival of semaglutide has sparked great enthusiasm in the field of mental health research. The proximal effect of weight-related cardiovascular disease is important in its own right. The secondary effect of semaglutide acting through neurogenesis and improving metabolic health may have an impact on other important outcomes such as cognition and quality of life, thereby filling an unmet need in the treatment of SMI,” Agarwal and Hahn added.

Exciting Opportunities

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

Research has shown significant evidence that certain drugs may help reduce dysfunctional inflammatory processes associated with a range of cognitive and psychiatric disorders, he added.

De Giorgi said many patients with mental illness also have physical health issues that lead to an increased risk of death. If these treatments improve mortality in patients with mental illness, it's important to understand that the specific mechanisms involved are secondary to the outcome. Psychiatrists must be equipped to prescribe, administer and initiate these treatments, he added.

“Trials in psychiatric patients are ongoing, but we are making progress and we should seize this opportunity,” DiGiorgi said.

Cryan agreed: “I think we'll get there. What these drugs have shown is that you can have a multitude of effects related to brain-body interactions through a single mechanism. Why not focus that on mood, anxiety or cognition? Either way, it's very exciting. What we need to do now are longitudinal, cross-sectional, placebo-controlled trials in specific patient populations,” he said.

The study was funded by the National Institute for Health and Care Excellence Oxford Health Biomedical Research Centre and the Medical Research Council. De Giorgi's co-authors reported 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.