A recent study of an international drug safety database – suggesting people taking semaglutide are likelier to think about suicide than those taking other drugs – is the latest see-saw of scientific evidence on the risk of depression and suicide tied to the popular medications, with critics saying the evidence is limited.
The use of semaglutide (brand name Ozempic when it’s prescribed for diabetes and Wegovy when prescribed for weight loss), has surged in recent years, and studies have shown more promising effects, including reductions in kidney disease and cancer, reports CNN.
However, between 2000 and 2023, it had 45% higher odds of suicidal ideation reports compared with all other drugs in the WHO database (reporting odds ratio [ROR] 1.45, 95% CI 1.18-1.77), according to Georgios Schoretsanitis, MD, PhD, of the Zucker Hillside Hospital in New York, and colleagues.
Last year’s reports of suicidality and self-harm with GLP-1 agonists to the FDA and European Medicines Agency (EMA) had triggered his group’s investigation, he added.
Several months after the first reports were received in the FDA’s Adverse Event Reporting System, the agency said its preliminary evaluation had “not found evidence” that GLP-1 receptor agonists cause suicidal thoughts or actions, but that it “cannot definitively rule out that a small risk may exist”, and that its investigation is ongoing, reports Medpage Today.
And earlier this year, the EMA confirmed it had found no evidence to support a causal link between GLP-1 receptor agonists and suicidal thoughts after a nine-month review.
Yet suicide has been a long-standing concern with medications that alter the desire for food.
For some people, losing the pleasure and reward of FOOD creates a dramatic shift in mood and may increase the risk of self-harm, and in 2008, the weight loss drug rimonabant, which acted on the same brain system that gives people the munchies when they’re on marijuana, was withdrawn from use because it increased the risk of suicide. (The drug was never approved for use in the United States.)
The patient information for semaglutide already includes a warning to be on the alert for depression and suicidal thoughts. But the evidence remains conflicting.
A large study published earlier this year in Nature Medicine found that semaglutide was linked to a lower risk of suicidal thoughts, compared with people taking different kinds of medications for weight loss and diabetes.
The latest study, published in JAMA Network Open, looked at reports of suicidal thoughts in people taking semaglutide – whether for diabetes or weight loss – in a database maintained by the WHO that compiles adverse events linked to drugs across 140 countries.
The study authors found 107 reports of patients, out of more than 30 500, who said they thought about killing themselves while taking semaglutide and 162 similar reports, out of more than 52 000, in patients taking liraglutide, a different injected diabetes medication in the same class as semaglutide. Liraglutide is an older drug, so more people have had experience taking it.
The authors found what they describe as a disproportional risk of suicidal thoughts in people taking semaglutide but not in people who were taking liraglutide.
When they compared reports of suicidal thoughts in people taking semaglutide with the risk reported with all other drugs in the database, they found that the risk was elevated by about 45% in people taking semaglutide.
The risk was about four times higher in people on medication to control depression and anxiety, suggesting this group may be at even higher risk for mood effects with these medications, they said.
When the authors excluded cases of people taking semaglutide and antidepressants, the association disappeared, suggesting that people who were taking both drugs were driving the risk.
The authors acknowledge that their research had limitations. But because so many people are taking semaglutide, they think the findings warrant further study and “urgent clarification” about the risk.
Other limitations of their research, they said, included an inability to determine whether weight change or other outcomes influenced the associations. There was also limited information about off-label prescribing, reports Medpage Today.
Schoretsanitis suggested future studies look at patients with a previous history of mental disorders or with comorbid mental disorders, including patients in clinical practice.
Other experts said the evidence presented in the study was thin.
“Basically, it is hard to tease out from this study whether it is the drug doing this or the mood disorder,” said Dr Mahyar Etminan, an expert in drug safety at the University of British Columbia in Vancouver who was not involved in the study.
“This paper presents, at best, weak evidence of an association between semaglutide and suicidality,” said Ian Douglas, a professor of pharmaco-epidemiology at the London School of Hygiene & Tropical Medicine. He said studies like this are good for generating theories but can’t prove cause and effect.
In a commentary on the study, Dr Francesco Salvo and Dr Jean-Luc Faillie, two French drug safety researchers who were not involved in the research, agreed.
They said it was common for drug safety studies to vary in their conclusions depending on the database used and the methods of the study. Until we have better evidence, it’s a good idea to be careful, they said.
“Depression or suicidality are rare but extremely severe events and need to be prevented and managed as much as possible,” Salvo and Faillie wrote.
Without more precise data, they think GLP-1 and other kinds of appetite suppressants should be prescribed with caution in people with a history of depression or suicidal thoughts. And if patients experience a new episode of depression while on the medication, they wrote, doctors may want to consider “immediate discontinuation”.
Study details
Disproportionality Analysis from WHO Sata on Semaglutide, Liraglutide, and Suicidality
Georgios Schoretsanitis, Stefan Weiler, Corrado Barbui, et al.
Published in JAMA Network on 20 August 2024
Abstract
Importance
Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have gained use primarily due to their weight-reduction effects, although a regulatory review was undertaken for potential suicidality concern.
Objectives
To evaluate potential signals for suicidal and self-injurious adverse drug reactions (ADRs) associated with the GLP-1 RAs semaglutide and liraglutide.
Design, Setting, and Participants
Disproportionality analysis through the case-control design using the World Health Organization (WHO) global database of suspected ADRs. Participants were clinical patients worldwide experiencing an ADR suspectedly attributable to semaglutide or liraglutide in the database from inception to August 30, 2023. Data were analyzed from September to December 2023.
Exposure
Treatment with semaglutide or liraglutide regardless of indication or treatment duration.
Main Outcomes and Measures
Reporting odds ratio (ROR) and the bayesian information component (IC) with 95% CIs were calculated as measures of disproportionate reporting of suicidal and self-injurious ADRs associated with semaglutide and liraglutide compared with all other medications. Sensitivity analyses were conducted including patients with coreported use of antidepressants and benzodiazepines and using dapagliflozin, metformin, and orlistat as comparators. A disproportionality signal was considered when the lower limits of the ROR and IC were above 1 and 0, respectively.
Results
A total of 107 (median [IQR] age 48 [40-56] years; 59 female patients [55%]) and 162 (median [IQR] age 47 [38-60] years; 100 female patients [61%]) cases of suicidal and/or self-injurious ADRs were reported between November 2000 and August 2023 with semaglutide and liraglutide, respectively. Significant disproportionality was detected only for semaglutide-associated suicidal ideation (ROR, 1.45; 95% CI, 1.18-1.77; IC, 0.53; 95% CI, 0.19-0.78), which remained significant in patients with coreported use of antidepressants (ROR, 4.45; 95% CI, 2.52-7.86; IC, 1.96; 95% CI, 0.98-2.63) and benzodiazepines (ROR, 4.07; 95% CI, 1.69-9.82; IC, 1.67; 95% CI, 0.11-2.65), when compared with dapagliflozin (ROR, 5.56; 95% CI, 3.23-9.60; IC, 0.70; 95% CI, 0.36-0.95), metformin (ROR, 3.86; 95% CI, 2.91-5.12; IC, 1.20; 95% CI, 0.94-1.53) and orlistat (ROR, 4.24; 95% CI, 2.69-6.69; IC, 0.70; 95% CI, 0.36-0.95).
Conclusions and Relevance
This study using the WHO database found a signal of semaglutide-associated suicidal ideation, which warrants urgent clarification.
See more from MedicalBrief archives:
No link between suicide and weight loss drugs – EMA
UK reviews weight-loss drugs after ‘suicidal thoughts’
European agency probes weight loss drugs’ link to suicidal thoughts
Patients felled by weight-loss drugs’ side effects