A growing body of research has done little to clear up concerns about whether there’s a link between GLP-1 drugs and depression, suicidal ideation and self harm.
The latest research, an observational study published earlier this month in JAMA, found there was an increased risk of suicidal ideation among patients who take Novo Nordisk’s semaglutide — marketed as Wegovy for weight loss — compared to other drugs. The study analyzed adverse event data gathered by the World Health Organization.
It showed that the risk of ideation was more pronounced in patients who were simultaneously taking antidepressants and GLP-1s. However, when the study excluded data from patients taking both GLP-1s and antidepressants, there was not a disproportionate relationship between semaglutide and suicidal thoughts.
Researchers and physicians are now questioning the study, which followed reports from European and US regulators earlier this year that did not find a link between the popular weight loss drugs and suicidal thoughts.
“The study is confounded by other effects such as weight loss,” said Amy Rothberg, a professor of internal medicine in the division of metabolism, endocrinology and diabetes at the University of Michigan. “We know that people who have lost weight experience a whole lot of changes related to their environment, social and work networks.”
Stephen Evans, a professor of pharmacoepidemiology at the London School of Hygiene & Tropical Medicine, took aim at the study via the Science Media Centre, a UK-based nonprofit that collects expert reactions to scientific issues. He described it as “not a significant or noteworthy paper” with “major limitations.”
“This paper is based just on spontaneous reports, which are sent to regulatory authorities in the country of the person reporting a suspected adverse reaction,” Evans said. “The evidence is extremely weak for a genuine effect in this instance.”
Other physicians cited by the Science Media Centre called for more studies.
“A call for caution and for further investigations in these groups of people, including those with pre-existing psychiatric disorders such as depression, is probably justified,” wrote Riccardo De Giorgi, a clinical lecturer in the department of psychiatry at the University of Oxford.
A spokesperson for Novo Nordisk told Endpoints News that the study has limitations that include “missing data on medication dose and treatment duration, limited ability to adjust for preexisting suicidal ideation or suicidal depression and alcohol and substance misuse, as well as a high proportion of off-label use.”
Confounding factors or a causal relationship?
The first concerns about a link between self-injury and suicidal thoughts and semaglutide emerged in 2023 out of the European Medicines Agency.
In April, though, the EMA concluded that there was no link between semaglutide and suicidal thoughts or actions following an investigation. The European regulator didn’t include newer drugs like Eli Lilly’s Zepbound in its investigation.
At the beginning of this year, the FDA said it found no evidence of a link in a preliminary review based on its Adverse Event Reporting System and review of clinical trials. An NIH-funded study also published early this year found a lower risk of suicidal ideation with semaglutide compared to other type 2 diabetes and obesity drugs.
Then, research released at the American Diabetes Association conference in Orlando earlier this summer showed there is not a causal relationship between the drug class and negative psychological effects. In some cases, it was the opposite.
In the population-based cohort study, researchers found that in more than 25,000 older adults with type 2 diabetes who were newly prescribed either GLP-1s or a dipeptidyl peptidase 4 inhibitor saxagliptin, GLP-1s were associated with a “significant decrease” in the risk of depression compared to the other inhibitor.
A second study looked at data out of the UK, again with newly-prescribed type 2 diabetes patients who were on GLP-1s or dipeptidyl peptidase-4 inhibitors. It found that GLP-1 use was not associated with an increased risk of suicide or self-harm. The researchers instead said it was “likely due to confounding factors rather than a causal relationship.”
A third study released at ADA by the same researchers as the population-based cohort study again looked at adults with type 2 diabetes. It found no “significant association” between GLP-1s and an increased risk of suicide or self-harm compared with participants on sodium-glucose cotransporter 2 inhibitors.
Rothberg told Endpoints News that the concerns coming out about suicidal ideation and GLP-1s could be because the drugs are being used “indiscriminately,” and patients’ health history — like having underlying anxiety and depression — isn’t being examined before a prescription.
She also pointed to the companies that are prescribing compounded drugs with an unknown purity and chemical makeup.
“There’s a wealth of data that in people who are appropriate for this drug, we’re just not really seeing that signal now,” Rothberg said. However, she added that because GLP-1 drugs target the hormone in the brain as well as serotonin, that could lead to anxiety early on in treatment.