Patients who take GLP-1 receptor agonists like semaglutide may be at higher risk of suicidal ideation compared with those taking other medications for diabetes and obesity, according to recent results from a study published in JAMA Network Open. However, two other studies recently published in JAMA Internal Medicine found no significant link between suicidality risk and use of GLP-1 receptor agonists.

In a case-control study published in JAMA Network Open, Georgios Schoretsanitis, MD, PhD, of the department of psychiatry at The Zucker Hillside Hospital, New York, and colleagues analyzed the rate of suicidal and self-injurious adverse drug reactions (ADRs) among patients taking either semaglutide or liraglutide in the WHO global database of suspected ADRs. The researchers assessed reporting of suicidal and self-injurious ADRs for GLP-1 receptor agonists when compared to medications such as dapagliflozin, metformin, and orlistat.

Out of 36,172,078 total reports in the database, there were 107 cases of suicidal and self-injurious ADRs for semaglutide and 162 cases for liraglutide reported between 2000 and 2023. The most common reasons for using semaglutide and liraglutide were potential off-label use (31.8% vs 33.9%), weight management (26.2% vs 24.7%), diabetes (24.3% vs 20.4%), and polycystic ovary syndrome (0.9% vs 0.6%).

The researchers found a significant disproportionality for semaglutide-associated suicidal ideation (reporting odds ratio [ROR] = 1.45; 95% CI, 1.18-1.77) compared with all other medications and also for patients who used antidepressants (ROR = 4.45; 95% CI, 95% CI, 2.52-7.86) and patients who used benzodiazepines (ROR = 4.07; 95% CI, 1.69-9.82). Semaglutide-associated suicidal ideation remained significant when the researchers compared them with patients who were receiving dapagliflozin (ROR = 5.56; 95% CI, 3.23-9.6), metformin (ROR = 3.86; 95% CI, 2.91-5.12), and orlistat (ROR = 4.24; 95% CI, 2.69-6.69). Drug discontinuation led to the resolution of suicidal ideation in 62.5% of cases, the researchers said.

As more people learn about GLP-1 receptor agonists through channels like social media, off-label use of these medications may increase, the researchers noted, and the risk for use of counterfeit medications also increases. “Recently, a public warning about fake counterfeit semaglutide pens was issued in the United Kingdom and the US. Considering the risk of suicidal ideation in people taking semaglutide off-label, authorities should consider issuing a warning to inform about this risk,” they said.

Citing a recent review by the European Medicines Agency (EMA) of liraglutide and semaglutide based on reports of suicidal or self-harming thoughts and the agency’s decision to not update the product information, Schoretsanitis and colleagues said “based on these findings, we believe that a precaution of use in patients with psychiatric disorders or psychological lability could be added in the semaglutide package insert.”

In a related editorial, Francesco Salvo, MD, PhD, of CHU de Bordeaux, France; and Jean-Luc Faillie, MD, PhD, of CHU Montpellier, France, echoed those concerns, and said the FDA’s position to exercise caution when prescribing GLP-1 receptor agonists “continues to be reasonable.”

“Whatever the cause, depression or suicidality are rare but extremely severe events and need to be prevented and managed as much as possible,” they wrote. “Waiting for more precise data, GPL-1 receptor agonists, and appetite suppressants in general, should be prescribed with great caution in patients with a history of depression or suicidal attempts, while in patients with new onset of depression without other apparent precipitants, immediate discontinuation of GLP-1 receptor agonists should be considered.”

Questions About GLP-RAs Still Remain

Two other studies recently published in JAMA Internal Medicine appear to contrast these findings. Thomas A. Wadden, PhD, of the department of psychiatry in the University of Pennsylvania, and colleagues conducted a post hoc analysis of 3,377 participants in the STEP 1, STEP 2, and STEP 3 trials, and 304 participants in the STEP 5 trial with overweight or obesity who received either 2.5 mg of semaglutide or placebo once per week for up to 68 weeks (STEP 1-3) or 104 weeks (STEP 5); a proportion of the participants in STEP 2 also had diabetes.

The researchers found Patient Health Questionnaire scores were similar at baseline and at 68 weeks for the semaglutide group (2 vs 2), which increased for the placebo group (1.8 vs 2.4), and there was an estimated between-group treatment difference of -0.56 (-0.81 to -0.32) (P < .001) favoring the semaglutide group. Participants receiving semaglutide were significantly less likely than the placebo group to change to develop a more severe depression category as measured by Patient Health Questionnaire scores (OR = 0.63; 95% CI, 0.5-0.79; P < .001), and there were no significant differences in likelihood of reporting suicidal ideation/behavior between groups as measured by Columbia-Suicide Severity Rating Scale scores. Researchers noted similar results in the STEP 5 trial.

“Most participants in both groups reported no change or improvement in their mood during the in-trial period, results that are similar to those observed with behavioral weight loss interventions,” Wadden and colleagues said.

In an active-comparator new-user cohort study, Peter Ueda, MD, PhD, of the division of clinical epidemiology at the Karolinska Institutet, Sweden, and colleagues evaluated the rate of death by suicide among 124,517 adults who started using a GLP-1 receptor agonist and 174,036 participants who started an SGLT2 inhibitor between 2013 and 2021 and were followed up for mean 2.5 years. Participants in the GLP-1 group most commonly used liraglutide (50%) and semaglutide (41%).

Overall, there were 77 suicides in the GLP-1 group (0.23 per 1,000 person-years) and 71 suicides in the SGLT2 group (0.18 per 1,000 person-years), with a hazard ratio (HR) of 0.83 for suicide death and non-fatal self-harm (95% CI, 0.7-0.97) and an HR of 1.01 for incident depression and anxiety (95% CI, 0.97-1.06).

“The findings indicate that the absolute risks of suicide death in broad groups of patients using GLP-1 receptor agonists are low and any potential risk increase would be small,” Ueda and colleagues wrote.

In an editor’s note, Timothy S. Anderson, MD, MAS, of the University of Pittsburgh; and Deborah Grady, MD, MPH, of the University of California, San Francisco, said the studies by Wadden and Ueda reinforce the conclusions of the FDA and EMA that there is “inadequate evidence” linking GLP-1 receptor agonists to suicidality, but noted that psychiatric safety questions about the drug class still remain. For instance, the studies did not assess whether symptoms are exacerbated in patients with pre-existing mental health problems, and other gastric inhibitory polypeptide/GLP-1 receptor agonists like tirzepatide were not analyzed.

“Given increased interest in studying GLP-1 receptor agonists for the treatment of substance use disorders and other conditions, continued vigilance in monitoring mental health symptoms is essential,” they concluded.

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Disclosures: Some authors declared financial ties to drugmakers. See full studies for details. The STEP trials were supported by Novo Nordisk.

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