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Treatment with GLP-1 receptor agonists was associated with lower risks of suicidal ideation or attempts in adolescents with obesity compared with those who were treated with lifestyle interventions, a retrospective cohort study suggested.

Among over 6,900 adolescents with obesity, treatment with GLP-1 drugs was associated with a 33% reduced risk for suicidal ideation or attempts over 1 year of follow-up compared with matched controls engaging in lifestyle interventions without GLP-1 therapy (1.45% vs 2.26%; HR 0.67, 95% CI 0.47-0.95, P=0.02), reported Liya Kerem, MD, MSc, and Joshua Stokar, MD, both of the Hebrew University of Jerusalem.

No signal for an increase in suicidal ideation or attempts associated with GLP-1 use was seen across subgroups stratified by sex, race and ethnicity, GLP-1 type, and diabetes status, as well as over a range of follow-up times up to 3 years, they noted in .

These findings are "reassuring," Kerem told 妖姬直播, noting that this was the first large-scale investigation into this association specifically among adolescents with obesity.

The study "contributes novel data to the existing literature, which previously lacked evidence regarding the psychiatric safety profile of GLP-1 receptor agonists in this age group," she said. "While our results do not establish causality, the finding of a decreased risk of suicidal behavior may alleviate some concerns stemming from individual case reports of increased suicidality."

The case reports in question prompted the FDA and European Medicines Agency (EMA) to launch investigations into the safety of this drug class used for type 2 diabetes, obesity, or both. GLP-1 drugs indicated for patients ages 12 and up with obesity currently include liraglutide (Saxenda) and semaglutide (Wegovy).

The FDA found no evidence to support a causal link between GLP-1 agonists and suicidality and self-harm in a preliminary evaluation. The EMA likewise to support a causal tie after its own 9-month review. Since then, more studies -- all in adult patients -- have also looked into this issue; some found an association and others did not.

As per current FDA guidance, GLP-1 drugs should be avoided in those with a history of suicide attempts and active suicidal ideation. The agency has also advised clinicians to monitor patients taking these drugs for new or worsening depression, suicidal thoughts, or any unusual changes in mood or behavior.

"It should be emphasized that causality cannot be inferred from our observational study design, and further research is necessary to validate these findings and investigate the underlying mechanisms that may contribute to the association," Kerem said. "Clinical decisions should always be individualized, taking into account each patient's unique situation."

For this study, Kerem and Stokar used electronic health records from the TriNetX global federated network from December 2019 to June 2024 featuring data from 120 mostly U.S.-based healthcare organizations. A total of 4,052 adolescents with obesity and a concomitant anti-obesity intervention were identified for the GLP-1 cohort and 50,112 were identified for the lifestyle intervention without GLP-1 therapy cohort. Suicidal ideation and attempts were identified using ICD-10 codes in health records.

Using propensity score matching, groups were balanced for several characteristics such as demographics, psychiatric medication use, psychiatric comorbidities, and diagnoses associated with socioeconomic status and healthcare access. This resulted in 3,456 participants in each balanced cohort.

Prior to propensity score matching, GLP-1 users were older (15.5 vs 14.7 years), and more likely to be female (59% vs 49%), have a higher body mass index (41.9 vs 33.8), and have a higher prevalence of diabetes (40% vs 4%). They also were more likely to have a history of psychiatric diagnoses (17% vs 9% for mood disorders) and psychiatric medication use (18% vs 7% for antidepressants).

Kerem noted that this suggests that GLP-1 receptor agonists "should not be categorically avoided in adolescents with obesity and psychiatric comorbidities, as the treatment may not pose an elevated risk in this context."

As expected with this drug class, there was a significantly higher rate of gastrointestinal symptoms among adolescents prescribed a GLP-1 agent (6.9% vs 5.4%; HR 1.41, 95% CI 1.12-1.78, P=0.003). There was no difference in the rates of upper respiratory tract infections between the groups.

In an alternative analysis starting 1 year before the index event, the researchers found no significant difference in the incidence of suicidal ideation or attempts between the groups (HR 0.93, 95% CI 0.55-1.57, P=0.79), "providing additional validation that the observed differences were more likely due to GLP-1 receptor agonist initiation than preexisting conditions."

The researchers said the incidence of suicidality was likely a low estimate due to the reliance on ICD codes, which reflect only those who sought treatment or disclosed suicidality to their clinician. However, this limitation "applies to both the study and control groups equally."

"It would be valuable for future research to include studies that directly examine psychiatric outcomes as primary endpoints," said Kerem. "Additionally, exploring the biological pathways through which GLPs may exert potential psychiatric effects could further clarify their role in this patient population."

If you or someone you know is considering suicide, call or text 988 or go to the .

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