DeutschMonthly Review Overview
At Erdem Hospital, the Pediatric Committee regularly evaluates new findings in childhood obesity research. This month’s focus is on a systematic investigation into the connection between GLP-1 therapy and increased risk of mental health disorders like depression, anxiety, and suicidal tendencies.
Study Overview
The analysis found that adults using GLP-1 receptor agonists to manage type 2 diabetes or obesity experienced higher rates of severe depression, anxiety, and suicidal thoughts or behaviors when compared to similar individuals who were not prescribed these medications.
Detailed Review
The application of GLP-1 receptor agonists (GLP1-RAs) for managing both obesity and type 2 diabetes has seen a significant surge in recent years. While these drugs demonstrate high effectiveness, concerns about their potential psychiatric side effects persist. In mid-2023, the European Medicines Agency initiated a review into whether GLP1-RA use could be linked to suicidal behaviors. In contrast, a safety evaluation by the U.S. FDA’s Adverse Event Reporting System did not establish such a link. Nonetheless, research findings remain mixed: while some trials—such as STEP-2 and STEP-6—report increased psychiatric risk with drugs like semaglutide and liraglutide, others, including a 2023 meta-analysis by Chen and colleagues, suggest a possible protective effect against depression.
This community-based retrospective cohort study examined how GLP1-RA usage influenced the onset of depression, anxiety, and suicidality over a five-year period. Researchers extracted ICD-10 codes from the TriNetX database to assess these outcomes. To reduce confounding variables such as demographic and socioeconomic differences, they employed propensity score matching. Participants in the treatment group were adults who received liraglutide (either Victoza 1.8 mg daily or Saxenda 3 mg daily) or semaglutide (Ozempic 1 mg weekly or Wegovy 2.4 mg weekly). The control group included adults with obesity who had not used GLP1-RAs and were matched accordingly. Both groups comprised 162,257 individuals. The index date was defined as either the start of GLP1-RA therapy or the date of an obesity diagnosis for controls. Individuals were excluded if they had a recent history (within one year prior or one month post index) of serious psychiatric disorders or prior GLP1-RA use.
The primary goal was to identify new psychiatric diagnoses—such as depressive disorders, anxiety, or suicidal behavior—occurring at least one month after treatment initiation. The study calculated hazard ratios to measure the psychiatric risks associated with GLP1-RA therapy.
Findings revealed a significantly elevated risk in the GLP1-RA group for all mental health conditions analyzed. The hazard ratio was 1.98 for any psychiatric disorder and 2.95 specifically for major depressive disorder—indicating that psychiatric issues were roughly twice as common, and depression nearly three times as prevalent, among GLP1-RA users. These risks persisted throughout the five-year follow-up, with consistently higher rates in the treated group. Subgroup analysis further broke down risks by demographic variables. Female patients faced the highest risk for major depressive disorder (hazard ratio 3.16). Suicidality risk peaked in those aged 18–49 (3.01), while depression was more prevalent in those aged 50–69 and above 70. Racial disparities also emerged: Black participants had the highest risks for suicidality (3.45), anxiety (2.03), and overall psychiatric illness (2.18); White participants had the highest depression risk (3.03); Asian individuals showed lower risk ratios, though they were underrepresented in the sample. Among the medications, Victoza showed the lowest psychiatric risk, while Wegovy showed the highest.
A key limitation of this study is the absence of BMI data, which may influence outcomes. Additionally, it did not account for medication adherence or adverse effects—factors that could have significantly impacted the findings. Despite these gaps, the results call for additional investigation. Notably, another study published in October 2024 using the same TriNetX database looked at adolescents aged 12–18 and found that GLP1-RA therapy was linked to lower risks of suicidal ideation and attempts compared to BMI- and propensity score-matched controls. This contradiction underscores the need for more targeted mental health research around these medications.
While obesity alone is known to elevate risks for depression, anxiety, and suicide, successful obesity treatments like GLP1-RAs would presumably lead to mental health improvements. One theory proposes that GLP1-RAs positively influence the brain’s dopamine system, potentially lowering addiction and improving psychological well-being. Conversely, some researchers suggest this interaction could dampen pleasure responses, possibly contributing to depressive symptoms and suicidal thoughts.
Ultimately, these results emphasize the need for a comprehensive, collaborative approach when managing obesity—one that includes mental health screening and ongoing monitoring. Although this particular study focused exclusively on adults, the findings highlight the importance of future adolescent-focused research on depression and anxiety. Given that adolescents eventually transition into young adulthood—an age bracket that showed elevated mental health risks in this study—it becomes even more critical to ensure continuity of care through a multidisciplinary support system.