medRxiv [Preprint]. 2025 Nov 13:2025.11.11.25339931. doi: 10.1101/2025.11.11.25339931.
ABSTRACT
IMPORTANCE: Rising rates of obesity and youth-onset type 2 diabetes (YT2D) in children and adolescents have increased GLP-1 receptor agonist (GLP-1 RA) use, raising concerns about potential effects on suicidal ideation/behaviors (SI/SB), depression, and anxiety.
OBJECTIVE: To assess associations between GLP-1 RA use for obesity or YT2D and risk of SI/SB, depression, and anxiety in children and adolescents.
SETTING: OneFlorida+ EHR from January 1, 2020, to January 31, 2024.
DESIGN: Retrospective cohort study using prevalent-new user design, target trial emulation framework, and sIPTW for confounding control.
PARTICIPANTS: Children and adolescents with obesity or YT2D who were ≥6 and <18 years were included with no history of the respective outcomes.
EXPOSURE: New GLP-1 RA users vs. Prevalent metformin users.
OUTCOMES: SI/SB, anxiety, and depression. Weighted Cox proportional hazards models were used to assess the risk of outcomes. Risk differences (RD) and hazard ratios (HR) are presented with 95% CI. RDs are per 1,000 person-years.
RESULTS: The study included 2,010, 1,774, and 1,764 patients for SI/SB, depression, and anxiety, respectively. The mean age was ∼14.2 years, ∼61% were female, with up to 4 years of follow-up, across cohorts. Compared to prevalent metformin users, GLP-1 RA users had lower incidence and risk of SI/SB (RD: -10.45, -14.54 to -6.36; HR: 0.11, 0.02 to 0.86) and depression (RD: -25.64, -34.90 to -16.39; HR: 0.37, 0.17 to 0.78). There was no difference in anxiety risk between the two groups (RD: 5.95, -7.10 to 19.01; HR: 1.13, 0.69 to 1.84).
CONCLUSIONS: GLP-1 RA use may reduce the risks of SI/SB and depression among children and adolescents with obesity or YT2D; no association was found with anxiety. Long-term surveillance is needed.
KEY POINTS: Question: Are GLP-1 receptor agonists (GLP-1 RAs) for the indication of obesity or youth-onset type 2 diabetes (YT2D) associated with the risk of mental health outcomes in children and adolescents?Findings: In this retrospective cohort study, including 2,116 children and adolescents with obesity or T2D, GLP-1 RA use was associated with a significantly lower risk of suicidal ideation and behaviors and depression when compared to prevalent metformin users. There was no significant difference in the risk of anxiety between the two groups.Meaning: The results of this study suggest that children and adolescents using GLP-1 RA for obesity or YT2D were at lower risk of suicidal ideation and behaviors, and depression compared to prevalent metformin users. The risk of anxiety remained non-significant, but the higher trend warrants future surveillance by pediatricians, psychologists, and pharmacoepidemiologists.
PMID:41292652 | PMC:PMC12642753 | DOI:10.1101/2025.11.11.25339931
