A disproportionality analysis of adverse drug reaction reports from the World Health Organization's global database identified a signal of increased suicidal ideation with the glucagon-like peptide-1 receptor agonist semaglutide.
The investigation, published in JAMA Network Open, found 107 cases, from over 30,500 total, of suicidal or self-injurious reactions associated with semaglutide, of which 7 (6.5%) were fatal. Suicidal ideation was reported in 94 cases (87.9%), with a mean treatment duration of 80.4 days before onset. Half of the suicidal ideation cases had no co-reported psychiatric symptoms. The signal remained in patients with co-reported antidepressant use, benzodiazepine use, and in a subanalysis of male patients.
No signal was found for liraglutide, another glucagon-like peptide-1 (GLP-1) receptor agonist included in the analysis, which had 162 associated suicidal or self-injurious reaction cases. Of these, 24 (14.8%) were fatal, and 116 (71.6%) involved suicidal ideation.
Sensitivity analyses also revealed disproportionate reporting of semaglutide-associated suicidal ideation when compared with the diabetes drugs dapagliflozin and metformin and the weight loss medication orlistat.
The median age of patients with suicidal or self-injurious reactions was 48 years for semaglutide and 47 years for liraglutide, with over half being female (55% and 62%, respectively). The most common indication was off-label use (32% for semaglutide and 34% for liraglutide), followed by weight management and diabetes.
The proportion of suicidal adverse reactions reported increased from 0% in 2017 to 0.8% in 2023 for semaglutide and from 0.09% in 2014 to 0.4% in 2023 for liraglutide.
"Whatever the cause, depression or suicidality are rare but extremely severe events and need to be prevented and managed as much as possible," noted authors in an invited commentary. "Waiting for more precise data, GPL-1 receptor agonists, and appetite suppressants in general, should be prescribed with great caution in patients with a history of depression or suicidal attempts, while in patients with new onset of depression without other apparent precipitants, immediate discontinuation of GLP-1 receptor agonists should be considered."
The findings come amid ongoing investigations by the European Medicines Agency and the U.S. Food and Drug Administration into GLP-1 receptor agonists and suicidality. The researchers noted limitations of the reporting data but said the detected signal "warrants urgent clarification," particularly given the high proportion of cases linked to off-label use.
Conflict of interests can be found in the published study.
