A Swedish national cohort study published in The Lancet Psychiatry found semaglutide was associated with a significantly lower risk of worsening depression, anxiety, and self-harm in patients receiving antidiabetic therapy, with liraglutide showing modest benefit.
Written by: Mennatullah Mansour, PharmD
Reviewed By: Dr, Bhavana Pandav-Wagh, MBBS,
MD-Psychiatry
A large national cohort study from Sweden suggests that certain GLP-1 receptor agonists, particularly semaglutide, are associated with a reduced risk of worsening mental illness in people with depression or anxiety who are receiving antidiabetic treatment. The findings, published in The Lancet Psychiatry, indicate that some agents in this class may offer dual metabolic and psychiatric benefits, although randomized trials are needed to confirm causality.
The study analyzed nationwide health register data from 95,490 individuals diagnosed with depression, anxiety, or both who used non-insulin antidiabetic medications between 2009 and 2022 (mean follow-up approximately 4 years). Researchers used a within-individual design, comparing periods when the same patient used GLP-1 receptor agonists with periods when they did not, reducing confounding from baseline patient differences. The primary endpoint was worsening mental illness, defined as psychiatric hospitalization, prolonged psychiatric sick leave, hospitalization due to self-harm, or suicide.
Semaglutide Shows Strongest Association
Semaglutide use was associated with a significantly lower risk of worsening mental illness compared with non-use (adjusted hazard ratio [aHR] 0.58; 95% CI 0.51–0.65). Liraglutide also showed a modest reduction (aHR 0.82; 0.76–0.89), while exenatide and dulaglutide showed no meaningful association. When compared directly with other GLP-1 receptor agonists, semaglutide remained linked to a lower risk of worsening psychiatric outcomes.
Secondary analyses showed that semaglutide was associated with reduced risk of worsening depression (aHR 0.56), anxiety (0.62), and substance use disorder (0.53). Liraglutide was associated only with reduced risk of worsening depression. Across the class, GLP-1 receptor agonist use was linked with a lower risk of self-harm (aHR 0.56).
Benefits Persist Across Sensitivity Analyses
The associations remained consistent after excluding early exposure periods, restricting analysis to post-approval timeframes, and comparing GLP-1 receptor agonists with other second-line antidiabetic therapies. When compared with empagliflozin, semaglutide was still associated with a reduced risk of worsening mental illness (aHR 0.73), supporting a drug-specific effect rather than a class effect.
The researchers also reported reductions in psychiatric hospitalization and sick leave. Semaglutide was associated with lower risk of inpatient psychiatric events (aHR 0.72) and psychiatric-related sick leave (0.55), while liraglutide showed smaller reductions in sick leave.
Interpretation and Clinical Context
Investigators concluded that semaglutide, and to a lesser extent liraglutide, were associated with significantly lower risk of worsening mental illness in individuals with depression or anxiety receiving antidiabetic therapy. The authors noted that the findings do not establish causality but provide a strong rationale for randomized trials evaluating potential dual benefits in metabolic and psychiatric outcomes.
They emphasized that the observed benefits were not seen with all GLP-1 receptor agonists, suggesting the effect is not uniform across the class. Potential mechanisms discussed include improved metabolic control, weight reduction, and direct neurobiological effects involving neurotransmission, neuroinflammation, and neuroprotective pathways. For instance, preclinical data suggest GLP-1RAs like semaglutide may modulate brain reward systems, reduce hypothalamic inflammation, and enhance synaptic plasticity effects that could explain benefits in depression and anxiety beyond glycemic control.
Overall, this long-term population analysis suggests that selected GLP-1 receptor agonists, particularly semaglutide, are associated with reduced risk of worsening depression, anxiety, and self-harm among people with metabolic disease. The authors note that the observational design prevents causal conclusions, and randomized controlled trials are needed to confirm potential dual metabolic and psychiatric benefits.
Reference
Heidi Taipale et al, Association between GLP-1 receptor agonist use and worsening mental illness in people with depression and anxiety in Sweden: a national cohort study, The Lancet Psychiatry, Volume 13, Issue 4 p327-335, April 2026, https://doi.org/10.1016/S2215-0366(26)00014-3
About the Writer
Mennatullah Mansour is pursuing a PharmD and is based in Alexandria, Egypt. She is driven by a strong passion for continuous learning and professional development, with a focus on pharmaceutical care, patient health, and medication safety. Her interests include prescription processing, patient counseling, and interpreting clinical information. She brings a detail-oriented approach and a strong ability to translate medical knowledge into clear, accurate, and reliable content for healthcare audiences.