Semaglutide Linked to Suicidal Ideation, New Study Reveals

Georgios Schoretsanitis, MD, PhD

Credit: ResearchGate

A recent study uncovered semaglutide may be linked to increased suicidal ideation.¹

“Until today, only a very recent cohort study using Market Scan data was sufficiently powerful to assess the risk of suicidality in real-life GLP-1 receptor agonist users,” wrote co-authors Francesco Salvo, MD, PhD and Jean-Luc Faillie, MD, PhD, in a commentary report.²

Glucagon-like peptide-1 receptor agonists semaglutide and liraglutide were originally approved to treat type 2 diabetes but later got approved for chronic weight management due to their weight loss properties.¹ Now, these two drugs are commonly prescribed for the latter indication. Investigators wanted to see if semaglutide and liraglutide were linked to the disproportionately increased reporting of suicidality.

Investigators, led by Georgios Schoretsanitis, MD, PhD, from The Zucker Hillside Hospital at Northwell Health in New York, conducted a disproportionality analysis through the case-control design using the World Health Organization (WHO) global database of suspected adverse drug reactions from November 2000 to August 30, 2023. The primary objective was to assess potential signals for suicidal and self-harm adverse drug reactions linked to semaglutide and liraglutide.

The sample included clinical patients worldwide who experienced an adverse drug reaction that was suspected to be attributed to semaglutide or liraglutide. Participants had a mean age of 48 years and 55% were female.

The main reason for a prescription was a possible off-label use (semaglutide: 31.8%; liraglutide: 33.9%), followed by weight loss (semaglutide: 26.2%; liraglutide: 24.7%), diabetes (semaglutide: 24.3%; liraglutide: 20.4%%), and 1 case for polycystic ovary syndrome for both semaglutide (0.9%) and liraglutide (0.6%).

In total, 107 participants on semaglutide had suicidal ideation or self-harm. Among these participants, the mean age was 48 years and 55% were female. A greater number of participants on liraglutide had suicidal ideation or self-harm (n = 162); the mean age of these participants was 47 years and 61% were female.

Despite more patients on liraglutide numerically reported suicidal ideation or self-harm, significant disproportionality was only detected for semaglutide-associated suicidal ideation (Reporting odds ratio [ROR], 1.45; 95% confidence interval [CI], 1.18 – 1.77). Semaglutide-associated suicidal ideation remained significant in patients who took antidepressants (ROR, 4.45; 95% CI, 2.52 0 7.86) and benzodiazepines (ROR, 4.07; 95% CI, 1.69 – 9.82) when compared to dapagliflozin (ROR, 5.56; 95% CI, 3.23 – 9.60), metformin (ROR, 3.86; 95% CI, 2.91 – 5.12), and orlistat (ROR, 4.24; 95% CI, 2.69 – 6.69).

“The number of reports showed a gradual increase over the years, which may indicate a widening therapeutic scope in obesity and accumulating clinical experience,” investigators wrote.

Despite the significant findings, investigators highlighted several limitations, including barriers to reporting and missing information, the inability to infer causality, the lack of a denominator which prevents accurate incidence estimates of adverse drug reactions, biases, and limited confounder adjustment. Other limitations included missing treatment outcomes such as weight change and preexisting suicidal ideation.

“In the meantime, the position of the US FDA recommending caution continues to be reasonable,” Salvo and Faillie wrote.² “Whatever the cause, depression or suicidality are rare but extremely severe events and need to be prevented and managed as much as possible.”

They continued to write how until there is more promising data, GPL-1 receptor agonists, and appetite suppressants should be prescribed with caution in patients with a history of depression or suicidal attempts.

“…based on these findings, we believe that a precaution of use in patients with psychiatric disorders or psychological lability could be added in the semaglutide package insert,” Schoretsanitis and colleagues wrote.¹ “Remarkably, the FDA label of semaglutide for obesity warned to monitor for depression or suicidal thoughts.”

References

1. ^{Schoretsanitis G, Weiler S, Barbui C, Raschi E, Gastaldon C. Disproportionality Analysis From World Health Organization Data on Semaglutide, Liraglutide, and Suicidality. JAMA Netw Open. 2024;7(8):e2423385. doi:10.1001/jamanetworkopen.2024.23385}
2. ^{Salvo F, Faillie J. GLP-1 Receptor Agonists and Suicidality—Caution Is Needed. JAMA Netw Open. 2024;7(8):e2423335. doi:10.1001/jamanetworkopen.2024.23335}