A recent observational study indicates that individuals taking popular GLP-1 receptor agonist obesity medications may face an elevated risk of developing mental health conditions, including depression and anxiety, as well as certain gastrointestinal issues. However, researchers caution that because absolute case numbers remain small and hospital-level results varied widely, the findings cannot prove that these medications directly cause psychiatric illness.
The joint study, conducted by research teams from Sungkyunkwan University’s College of Pharmacy and Ajou University College of Medicine, was published in the international academic journal Diabetes, Obesity and Metabolism. The team analyzed real-world electronic medical records (EMR) across 13 secondary and tertiary medical institutions in South Korea to evaluate the real-world safety profiles of semaglutide (marketed as Wegovy) and liraglutide (marketed as Saxenda).
GLP-1 class medications function by mimicking appetite-regulating hormones to increase satiety and suppress hunger, aiding in weight loss and blood sugar management. While randomized clinical trials have confirmed their safety and efficacy, data regarding side effect patterns in routine clinical settings has remained limited.
To bridge this gap, the researchers examined outcomes among patients prescribed these drugs for weight management. The study evaluated a cohort of 2,357 Wegovy users against a 22,602-person control group, alongside 6,953 Saxenda users compared with a 68,001-person control group.
The 13 participating medical centers included Ajou University Hospital, Chung-Ang University Hospital, Ewha Womans University Medical Center, Soonchunhyang University Bucheon Hospital, Soonchunhyang University Cheonan Hospital, Kyung Hee University Hospital, Kangwon National University Hospital, Hallym University Dongtan Sacred Heart Hospital, Gangdong Sacred Heart Hospital, Catholic Kwandong University International St. Mary’s Hospital, Wonkwang University Hospital, Keimyung University Dongsan Hospital, and Myongji Hospital.
Statistical Risk Spikes vs. Real-World Variance
The analysis revealed that patients prescribed Wegovy exhibited higher relative risks for specific psychiatric and gastrointestinal conditions compared to the control group. Overall, the risk of developing mental disorders was roughly two times higher, with anxiety disorders 2.39 times higher and depressive disorders 3.42 times higher. Additionally, risks for gastrointestinal motility disorders or obstructions were 3.91 times higher, while visual impairment risks were 1.58 times higher.
However, researchers noted significant statistical caveats. For example, gastrointestinal motility disorders and obstructions occurred in only six total cases within the Wegovy cohort, introducing substantial statistical uncertainty regarding the true magnitude of risk.
Similarly, while the overall risk of depressive disorders appeared 3.42 times higher across the aggregated dataset, this spike was predominantly driven by data from just two of the 13 hospitals. The increased rate of depression was not consistently observed across the remaining institutions, indicating that regional or hospital-specific diagnostic variables may have influenced the calculation.
Saxenda, which entered the South Korean market earlier, demonstrated a similar pattern. Compared to non-users, Saxenda patients showed a 1.7-fold increase in overall mental health disorder risk, a 1.68-fold increase in anxiety disorders, and a 1.51-fold increase in depressive disorders. As with Wegovy, the degree of risk variation across individual hospitals was considerable.
Correlation, Not Causality: Why Observational Limits Matter
The research team acknowledged a biological basis for potential central nervous system effects, as GLP-1 receptors are expressed in brain regions that regulate mood and behavior. Nevertheless, they emphasized that the study's design prevents drawing any conclusion of direct causality.
Because the investigation relied on observational retrospective medical records, it could not control for all baseline variables. Notably, body mass index (BMI)—a primary indicator of obesity severity—could not be incorporated as a variable due to data constraints in EMR records. Consequently, the team could not isolate whether pre-existing psychological stress or severe obesity itself contributed to the depressive symptoms.
Furthermore, randomized controlled trials (RCTs)—the gold standard for clinical evidence—have to date found no definitive evidence that GLP-1 receptor agonists cause or exacerbate depression or suicidal ideation. Medical experts also note that off-label misuse and cosmetic abuse of obesity drugs among non-obese individuals remain significant public health concerns that complicate observational data.
"In this study, it is possible we were not able to completely filter out pre-existing conditions participants had prior to starting medication," the research team stated. "Future evaluations must comprehensively account for individual patient characteristics, weight trajectories, and concurrent prescriptions."
