A new observational study found that people taking Ozempic and Wegovy appeared to experience suicidal thoughts at a higher rate than people on other drugs, though experts raised concerns about the methodology and the findings contradict what some other studies have found about the class of GLP-1 diabetes and obesity drugs.
Academic researchers analyzed a World Health Organization database that tracks suspected adverse drug reactions, and found that there was a 45% greater rate of reports of suicidal thoughts associated with semaglutide, the ingredient in Novo Nordisk’s Ozempic and Wegovy, compared with all other drugs in the database.
When comparing semaglutide specifically against other diabetes and obesity drugs — including Farxiga, metformin, and orlistat — the reseachers again saw a higher rate of suicidal ideation reported for semaglutide, according to the study, published Tuesday in JAMA Network Open.
These observations do not mean that semaglutide caused suicidal thoughts, and the overall rate of those thoughts occurring was still small, making up only 0.3% of all the adverse reactions reported for semaglutide. Additionally, while semaglutide was linked to a higher rate of suicidal thoughts versus other drugs in the database, it was linked to a lower rate of behaviors such as suicide attempts and self-injury.
Notably, the researchers did not find a higher rate of suicidal thoughts tied to an older and less effective GLP-1 drug from Novo called liraglutide, the ingredient in the diabetes treatment Victoza and the obesity therapy Saxenda.
The new study is part of an emerging mixed picture of whether the highly popular GLP-1 drugs are linked to a greater risk of suicidal ideations. One other observational study saw an increased rate associated with GLP-1 drugs (though not a causal relationship), while other studies have not. The Food and Drug Administration and the European Medicines Agency have looked into the issue, following anecdotal reports of suicidal thoughts, but they so far have not found evidence of a causal link.
Some obesity drugs that came before the GLP-1 treatments were associated with a greater risk of suicidal ideations, leading doctors and regulators to watch out for a similar phenomenon when evaluating new obesity drugs. The label for Wegovy — which is approved for obesity — already warns doctors to monitor patients for suicidal thoughts; the label for Ozempic — approved for diabetes — doesn’t.
In a statement, Novo said, “the known risks associated with use of these medicines are reflected in their current FDA- and EMA-approved product labeling.” The company said it stands by the safety and efficacy of its GLP-1 drugs when they’re used as indicated, and it continues to collaborate with regulators to monitor the safety of its treatments.
Novo, as well as external experts, noted that the new study is limited since it doesn’t control for variables such as how well patients adhered to treatment and patients’ diagnoses and medical histories.
Rodrigo Mansur, an assistant professor of psychiatry at the University of Toronto who wasn’t involved in the study, said this issue needs further study and it’s possible that there is a specific subset of patients who might be at risk of suicidal thoughts when taking the drugs, and not the entire population.
At the same time that regulators are looking into the issue, researchers are also examining a different potential effect of GLP-1 drugs — whether they might actually help treat mental health disorders. Mansur is running a clinical trial to see if semaglutide can improve cognitive function in people with obesity and major depression.
He said it’s not inconceivable that GLP-1 drugs benefit certain people with mental health disorders while increasing risks for some others — much in the way that standard antidepressants can be helpful for many people but may also increase the risk of suicidal thinking in others.
In the new study, the reseachers found that there was a higher rate of suicidal thoughts reported particularly by patients who were taking both semaglutide and antidepressants — greater than four times the rate for other drugs in the database. When researchers excluded those patients from their analysis, semaglutide was no longer linked to a greater rate of suicidal ideations.
There are many possible explanations for this finding. It could be that the combination of semaglutide with antidepressants increases the risk of suicidal thinking. It could also be that once the people taking both drugs were excluded from the analysis, the sample size was too small to perform meaningful statistical analyses.
Or, it could point to a confounding variable — it’s possible that people on semaglutide were already at higher risk of depression and suicidal ideations even without semaglutide, as diabetes and obesity are conditions that increase the risk of depression.
Rong Xu, a professor of biomedical informatics at Case Western Reserve University who was not involved in the study, said over email that “the database and method have limitations, which are all related to unmeasured or uncontrolled confounders.”
Xu said the WHO database used in this new study does not include comprehensive information on patients’ demographics, lifestyle factors, and medical history, which are all potential confounders that are not fully accounted for in the research. Xu had led a different study that did not find a link between GLP-1 drugs and suicidal ideations, using a different database.
Experts also questioned whether it’s the drugs themselves or the weight loss that might lead to suicidal thinking. Whenever a person loses a significant amount of weight, they’re going through a significant life change that could affect their mental health. Or, if patients are expecting to lose a lot of weight, but don’t, the disappointment may worsen their mental health as well, particularly since semaglutide’s efficacy has been highlighted so much in the media.
Stephen Burgess, group leader at the MRC Biostatistics Unit at University of Cambridge who was not involved in the study, said in a statement that “the impact of losing a large amount of weight could have negative emotional consequences. If an individual thinks that losing weight is the key to happiness, but losing weight does not bring happiness, could this lead to depression and suicidal ideation?”
“We need to understand whether these results represent a specific side-effect of these drugs, or an uncommon but tragic consequence of some individuals’ weight loss journey,” he added.
If you or someone you know may be considering suicide, contact the 988 Suicide & Crisis Lifeline: call or text 988 or chat 988lifeline.org. For TTY users: Use your preferred relay service or dial 711 then 988.