These drugs appear to be safe for patients without mental health diagnoses, but questions remain.

Observational data have suggested a link between glucagon-­like peptide-­1 (GLP-­1) receptor agonists and severe depression; however, convincing evidence of causation has not been found (NEJM JW Gen Med Jun 1 2024). Earlier this year, the US Food and Drug Administration (FDA) released a statement that a preliminary review of case reports showed ‘no clear relationship’ between suicidality and use of GLP-1 agonists.

Three new studies add further insight, as follows:

• in a retrospective study from Sweden and Denmark, researchers used nationwide data to compare suicidality among patients who started GLP-1 agonists versus those who started sodium-glucose cotransporter-2 (SGLT-2) inhibitors. Among 300,000 patients, suicidality did not differ between the two groups during mean follow up of about 2.5 years. Only about 1.5% of patients had diagnoses of depression or anxiety in the year prior to drug initiation
• in a study drawn from the placebo-controlled, randomised trials that informed FDA approval of semaglutide (with about 700 patients), researchers found no evidence of worsening depression or suicidality during 68 weeks of follow up. However, patients with histories of depression, severe psychiatric disorders or suicidal ideation were excluded
• in a case-control study using a WHO pharmacovigilance database, semaglutide but not liraglutide was associated with a disproportionate number of suicidality reports. Disproportionality was not present when researchers excluded antidepressant users.

Comment: Taken together, these studies suggest that GLP-1 agonists are not associated with depression or suicidality in patients without mental health diagnoses. However, the positive association with suicidality in the pharmacovigilance database and the probability of comorbid depression in patients with suicidality is troubling given our lack of knowledge about the safety of these drugs in patients with mental health disorders. My take is that clinicians should obtain mental health histories prior to initiating GLP-1 agonists, screen for depression and proactively discuss possible mental health risks with their patients.

Christopher W. Goodman, MD, Clinical Assistant Professor of Internal Medicine, University of South Carolina School of Medicine, Columbia, USA.

Ueda P, et al. GLP-1 receptor agonist use and risk of suicide death. JAMA Intern Med 2024 Sep 3; e-pub (https://doi. org/10.1001/jamainternmed.2024.4369). Wadden TA, et al. Psychiatric safety of semaglutide for weight management in people without known major psychopathology: post hoc analysis of the STEP 1, 2, 3, and 5 trials. JAMA Intern Med 2024 Sep 3; e-pub (https:// doi.org/10.1001/jamainternmed. 2024.4346).

Schoretsanitis G, et al. Disproportionality analysis from World Health Organization data on semaglutide, liraglutide, and suicidality. JAMA Netw Open 2024; 7: e2423385.