Pediatric Research Update: The Risk of Depression, Anxiety, and Suicidal Behavior in Patients With Obesity on Glucagon Like Peptide-1 Therapy

Each month, the OMA Pediatric Committee reviews a pediatric-focused obesity research update to help keep you up to date about the latest findings. This month’s update refers to a systematic review of the risk of depression, anxiety, and suicidal behavior in patients on glucagon like peptide-1 therapy.

Article Summary

Risk of major depression, anxiety, and suicidal ideation or attempts were increased in adults who took glucagon like peptide-1 receptor agonist medication for type 2 diabetes or obesity compared with propensity score matched adults with obesity who did not take this medication.

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Article Review

Glucagon like peptide-1 receptor agonist (GLP1-RA) use for treatment of type 2 diabetes mellitus as well as obesity has been skyrocketing. While these medications are extremely effective, some questions still linger regarding potential adverse effects. In July 2023, the European Medicines Agency released a statement regarding an investigation into a potential association between GLP1-RA treatment and increased risk of suicidality. Ultimately, the US Food and Drug Administration Adverse Event Reporting System found no association between the two. However, the literature presents a mixed picture. Some studies have shown an increased risk of psychiatric events in patients taking semaglutide (STEP-2, STEP-6) and liraglutide1 compared with placebo, whereas others have shown a protective effect against depression, including a 2023 meta-analysis by Chen et al2.

This retrospective community-based cohort study assessed the risk of development of depression, anxiety, and suicidal behavior following initiation of GLP1-RA treatment over a 5 year follow-up period. ICD10 codes were extracted from the TriNetX database for each of the variables and outcomes studied. The study utilized propensity score matching to reduce confounding by variables such as age, sex, race, economic circumstances, and psychiatric comorbidities. The intervention group was comprised of adult patients who had a prescription for liraglutide (Victoza 1.8 mg SQ daily or Saxenda 3mg SQ daily) or semaglutide (Ozempic 1mg SQ weekly or Wegovy 2.4 mg SQ weekly), and the control group was comprised of adult patients with obesity who did not have a prescription for a GLP1-RA during that time period and were matched to the intervention group by propensity score matching. 162,257 patients from each group were evaluated, with the index date being either the date they started GLP1-RA treatment or the date of the obesity diagnosis for controls. Anyone with a diagnosis of bipolar disorder, schizophrenia, depressive disorders, anxiety, and/or suicidal ideation/attempts within 1 year before or 1 month after the index date, or who had a prior use of GLP1-RA was excluded. The primary outcome was the first occurrence of any psychiatric disease: depressive disorders, anxiety, suicidality (ideations, attempts, intentional self harm) starting at least one month after the index date. Risk ratios were calculated to compare risk of psychiatric outcomes associated with GLP1-RA therapy.

The study found a significantly higher risk of all psychiatric outcomes studied in the GLP1-RA group, ranging from a hazard ratio of 1.98 for any psychiatric disease to 2.95 for major depressive disorder, meaning that about twice as many patients on GLP1-RAs developed any psychiatric outcome and about 3 times as many were diagnosed with depression compared with controls. The rates of psychiatric diagnosis increased progressively over the 5 year period in both groups, however the risk remained significantly higher in the GLP1-RA group at all time points. The authors also reported subgroup analyses which stratified risk ratios by age, sex, race, and different GLP1-RAs. Notably, higher risk ratios for all outcomes were reported in women, of which major depressive disorder was the highest (3.16). 18-49 year olds had the highest risk ratios for suicidality (3.01), anxiety (2.16), and any psychiatric disease (2.01), whereas major depressive disorder risk ratio increased with older age groups (2.44, 2.49 for 50-69 and 70+ respectively). When stratified by race, Blacks had the highest risk ratio for suicidality (3.45), anxiety (2.03), and any psychiatric disorder (2.18), Whites had highest for major depressive disorder (3.03), and Asians had lower risk ratios for all outcomes but had generally low numbers in the study population. Among the individual GLP1-RAs, Victoza had the lowest risk ratios, and Wegovy the highest.

One significant limitation of the data presented in this study is that BMI was not evaluated. Medication side effects and compliance were also not assessed. Thus, it is possible that these results may be confounded by medication adverse effects, compliance, or response. Nonetheless, the findings of study warrant further investigation. Interestingly, a study also published in October 2024 utilizing the same database but investigating suicidality in adolescents found a decreased risk of suicidal ideation and attempts in adolescents age 12-18 years with obesity treated with GLP1-RAs compared with propensity score and BMI matched controls3. This further underscores the need to investigate the effects of GLP1-RA therapy on mental health. It is well known that obesity alone increases risk of depression, anxiety, and suicidality. It then would make sense that by effectively treating obesity, mental health would improve with GLP1-RA therapy. Further, GLP1-RA is postulated to affect the brain’s dopaminergic reward system and decrease risk of addiction, which can further improve mental health. On the other hand, it is also theorized that this interference with the dopaminergic system can lead to symptoms of anhedonia and explain why GLP1-RA therapy can lead to depressive and suicidal symptoms.

In addition to highlighting the need for further research, the findings of this and other studies demonstrate the importance of a multidisciplinary approach to obesity treatment and a thorough evaluation of a patient’s psychosocial history as well as close monitoring throughout the course of treatment and beyond. While this study only included adults, the findings suggest the need to perform similar studies in adolescents regarding major depression and anxiety outcomes. Further, these adolescents will become young adults and given the highest risk of anxiety and suicidality in this age group, it further underscores the importance of ensuring transition of care in a multidisciplinary manner.

1. Astrup, A. et al. Safety, tolerability, and sustained weight loss over 2 years with the once-daily human GLP-1 analog, liraglutide. Int J. Obes, 2012.
2. Chen, X. et al. The antidepressant effects of GLP-1 receptor agonists: a systematic review and meta-analysis, Am J Geriatr Psychiatry, 2023
3. Kerem L and Stokar J. Risk of Suicidal Ideation or Attempts in Adolescents with Obesity Treated with GLP1 Receptor Agonists. Jama Pediatrics, 2024