Defying Earlier GLP-1 Data, Study in Teens Sees Possible Mental Health Gains

In teens with a diagnosis of obesity, glucagon-like peptide-1 (GLP-1) receptor agonists may lower the risk of suicidal ideation or attempts, a retrospective cohort study suggests.

Compared with those prescribed lifestyle intervention for obesity, adolescents prescribed either liraglutide (Saxenda; Novo Nordisk) or semaglutide (Wegovy; Novo Nordisk) had a 33% lower risk of suicidality over 12 months of follow-up after controlling for potential baseline confounders.

“Our findings provide additional evidence in line with regulatory conclusions that current data do not support a causal link between GLP-1 [receptor agonist] use and increased psychiatric risk,” Liya Kerem, MD (Hadassah University Medical Center, Jerusalem, Israel), told TCTMD.

“However, it's important to note that previous smaller studies offered mixed results, often without focusing specifically on adolescents. Our study contributes a novel and important perspective by examining a large cohort of adolescents, but further research is still needed to confirm and expand upon these findings,” she said in an email.

As previously reported by TCTMD, those prior studies prompted both the US Food and Drug Administration and the European Medicines Agency to investigate the association between GLP-1 drugs and suicide. In January 2024, the FDA concluded that based on data from their Adverse Event Reporting System they could not find an association between use of GLP-1 agents and suicidal thoughts or actions. In April 2024, the European regulators reached a similar conclusion.

However, in August 2024, the World Health Organization  suggested that semaglutide, but not liraglutide, may be associated with suicide and self-injury based on an analysis of individual case safety reports from its postmarketing surveillance database.

In addition to aligning with regulatory conclusions, the new study by Kerem and co-author Joshua Stokar, MD (Hadassah University Medical Center), adds to other analyses suggesting favorable mental health effects of GLP-1 receptor agonists, including one that showed a lower risk of incident and recurrent suicidal ideation in adults who were overweight or obese and taking semaglutide and another that showed no causal link between semaglutide or liraglutide and reporting of suicidal ideation and depression.

Of note, the current study did not include adolescents taking tirzepatide (Mounjaro and Zepbound; Lilly), because it is only approved for adults aged 18 and older.

In the paper, published October 14, 2024, in JAMA Pediatrics, Kerem and Stokar say they suspect that there are several explanations to support a favorable psychiatric profile of GLP-1 receptor agonists, including the ability of the medications to contribute to improvements in quality of life and psychiatric comorbidities associated with obesity.

No Signal Seen

For the study, the researchers compared anonymized electronic health records of 54,164 patients ages 12 to 18 years who had a diagnosis of obesity. Of those, 4,052 were prescribed a GLP-1 receptor agonist. Compared with controls, those prescribed medication were slightly older (mean 15.5 years vs 14.7 years), more often female, had higher body mass index, higher prevalence of diabetes and use of antidiabetic medications, as well as a history of psychiatric diagnoses and use of psychiatric medications. Propensity-score matching yielded 3,456 pairs.

At 12 months of follow-up, diagnosed suicide attempts or reported suicidal ideation occurred in 1.4% of the GLP-1 group and 2.3% of controls (HR 0.67; 95% CI 0.47-0.95).

As expected, patients in the medication group had more GI symptoms than did controls (6.9% vs 5.4%; P = 0.003).

In analyses stratified by sex, race, ethnicity, GLP-1 drug type, and diabetes status over a range of follow-up times, there was no signal of increased suicidal ideation or attempts associated with GLP-1 prescription.

Additionally, an analysis starting 1 year before the index event had no impact on the primary outcomes, which the researchers say provided “additional validation that the observed differences were more likely due to GLP-1 receptor agonist initiation than preexisting conditions.”

To TCTMD, Kerem said while it is not possible to infer causality from the findings, the reduced hazard ratio is reassuring, particularly in light of the known increased risk in adolescents with obesity—apart from any medication use—of suicidal ideation and behavior. Data from the National Vital Statistics Reports in December 2023 indicated that suicide is the second most prevalent cause of death in youth, Kerem and Stokar note in the paper.

At this point, Kerem said it’s a fair assessment to conclude that the impact that GLP-1 therapies have on mental health is likely to be multifactorial, with favorable effects on both body weight and addiction centers in the brain.

“While the weight loss associated with GLP-1 [receptor agonist] treatment may indeed improve body image and overall mental health, other potential mechanisms could also be at play,” she said. “These may include effects on neuroinflammation and neural pathways related to reward and food addiction. However, these remain preliminary, and further research is necessary to explore these pathways in depth and establish any direct connections.”