¹University of Eastern Finland, Forensic Psychiatry, Kuopio, Finland, ²Karolinska Institutet, Clinical Neuroscience, Stockholm, Sweden, ³Griffith University, School of Medicine and Dentistry, Gold Coast, Australia, ⁴The Edinburgh Practice, Edinburgh, United Kingdom, ⁵Niuvanniemi Hospital, Forensic Psychiatry, Kuopio, Finland

Background: Individuals with diabetes have an elevated risk of developing depression, anxiety, and suicide. Glucagon-like peptide-1 receptor agonists (GLP-1RA) are licensed to treat diabetes and obesity but data on whether GLP-1RA alleviate or exacerbate anxiety, depression, and self-harm are mixed.

Aims & Objectives: We studied the risk of worsening mental illness in people already diagnosed with depression and/or anxiety who were prescribed antidiabetic medications including GLP-1RA.

Method: We conducted a nationwide cohort study utilizing the national Swedish register. We included people with a diagnosis of depression (ICD-10: F32-F33) or anxiety disorder (ICD-10: F40-F43) who used any antidiabetic medication, between the years 2009-2022. Individuals with a diagnosis of schizophrenia (ICD-10: F2X) or bipolar disorder (ICD-10: F30-F31) were excluded. We modeled the medication use of the study participants using the PRE2DUP-method based on pharmacy dispensings. Use of GLP-1RA individually and as a group were compared with non-use of GLP-1RA, and directly with other second-line antidiabetic medications. A within-individual design was utilized for all comparisons to reduce confounding. The main outcome was worsening of mental illness, defined as a combination of any psychiatric hospitalisation (ICD-10 F00-F99); sick leave because of psychiatric problems; hospitalization due to self-harm; or death by suicide. Within-individual stratified Cox models with adjusted Hazard Ratios (aHR) and 95% confidence intervals (CIs) were used.

Results: The cohort included 95490 people (56976 women, 38514 men) with a mean age of 51 years (SD 12.3). GLP1-RA were used by 22480 study participants during the follow-up period. Semaglutide was associated with a 42% lower risk of worsening mental illness (aHR 0.58, 95%CI 0.51-0.65), and liraglutide with an 18% decreased risk (aHR 0.82, 95%CI 0.76-0.89), compared with non-use of GLP-1RA. Exenatide and dulaglutide were not linked with a reduced risk. Semaglutide was associated with a 44% decreased risk of worsening depression, a 38% lower risk of worsening anxiety, and 47% lower risk of worsening substance use disorder. GLP-1RA as a group were associated with a reduced risk of self-harm (aHR 0.56, 95%CI 0.34-0.92).

Discussion & Conclusions: GLP-1RAs may improve depression and anxiety, and clinicians should be mindful of this dual effectiveness given how frequently depression and anxiety co-exist with diabetes and obesity. Randomised controlled trials further testing these associations of dual effectiveness are warranted.