Swedish national cohort finds semaglutide linked to lower risk of worsening mental illness

A national cohort study published in The Lancet Psychiatry found that people with depression or anxiety who were taking antidiabetic medication had a lower risk of their mental illness worsening during periods when they were using semaglutide, compared with periods when they were not ^[1][2]. The same pattern appeared, more weakly, for liraglutide. Two older GLP-1 drugs, exenatide and dulaglutide, showed no association ^[2].

Researchers pulled the cohort from Swedish national health registers. It included 95,490 people diagnosed with depression or an anxiety disorder who used any antidiabetic medication between 2009 and 2022 ^[2]. The group was 56,976 female (59.7%) and 38,514 male (40.3%), with a mean age of 50.6 years (standard deviation 12.3) ^[2]. Ethnicity data were not available ^[2]. During follow-up, 22,480 people used a GLP-1 receptor agonist ^[2].

What the study measured

The main outcome was a composite called "worsening of mental illness": psychiatric hospitalization, sick leave from work lasting more than 14 days for psychiatric reasons, hospitalization for self-harm, or death by suicide ^[2]. Secondary outcomes included worsening depression and worsening anxiety analyzed separately, worsening substance use disorder, and self-harm ^[2].

Compared with periods of non-use of GLP-1 receptor agonists, semaglutide was associated with an adjusted hazard ratio of 0.58 (95% CI 0.51–0.65) for worsening mental illness, and liraglutide with 0.82 (0.76–0.89) ^[2]. Exenatide (1.01, 0.69–1.46) and dulaglutide (1.01, 0.85–1.20) showed no association ^[2]. A hazard ratio of 0.58 means roughly a 42% lower rate of the outcome during treated periods; the confidence interval shows the range statistically compatible with the data.

For the secondary outcomes, semaglutide was linked to lower risk of worsening depression (0.56, 0.44–0.71), worsening anxiety (0.62, 0.52–0.73), and worsening substance use disorder (0.53, 0.35–0.80) ^[2]. Liraglutide was associated only with lower risk of worsening depression (0.74, 0.64–0.87) ^[2]. Taken as a single group, GLP-1 receptor agonists were associated with a reduced risk of self-harm (0.56, 0.34–0.92) ^[2].

The study used a within-individual design, comparing periods when the same person was using a medication with periods when they were not, analyzed with within-individual stratified Cox models ^[2]. That approach reduces confounding from fixed traits such as genetics, baseline psychiatric severity, or long-standing lifestyle differences between people. It does not remove confounding from things that change over time, such as someone starting a GLP-1 drug during a stretch when they already felt better or had more contact with health care. The authors themselves wrote that randomized controlled trials evaluating these findings are warranted ^[2].

The authors' interpretation was that for anxiety and depression co-occurring with diabetes and obesity, semaglutide and, to a lesser extent, liraglutide "might be useful dually effective therapeutic options" ^[2]. The work was funded by the Sigrid Jusélius Foundation, the Jane and Aatos Erkko Foundation, and the Finnish Ministry of Social Affairs and Health ^[2]. Several authors reported personal fees or research funding from drug companies including Janssen, Lundbeck, Otsuka, and others; one author declared no competing interests ^[2]. A person with related lived experience was involved in the study's design and write-up ^[2].

Why it matters for patients

Questions about GLP-1 drugs and mental health have followed these medicines for years, and the study authors note that existing data on whether they alleviate or worsen anxiety, depression, and self-harm are mixed ^[2]. This analysis adds large-scale, real-world evidence pointing away from harm and toward possible benefit for people who already carry a depression or anxiety diagnosis.

A few limits are worth holding onto. Everyone in this cohort was using antidiabetic medication, so the findings may not transfer directly to people taking semaglutide or tirzepatide purely for weight management ^[2]. The outcomes measured were severe events — hospitalization, extended psychiatric sick leave, self-harm, suicide — not day-to-day mood scores ^[2]. And the study did not examine tirzepatide (Mounjaro/Zepbound) or orforglipron (Foundayo); only semaglutide, liraglutide, exenatide, and dulaglutide were reported ^[2].

An observational study cannot establish that semaglutide caused the lower risk. Nothing here changes labeling, prescribing rules, or coverage in the United States.

What happens next

The paper calls for randomized controlled trials to test whether the association holds up under experimental conditions ^[2]. No such trial timeline is described in the published abstract, and whether any is planned is not yet known from these sources.