Thomas A. Wadden, PhD: Semaglutide Not Linked to Increased Depression Risk

A recent post-hoc analysis showed taking semaglutide for weight management does not increase the risk of depression or suicidal thoughts in individuals without a known major mental health disorder.^1,2

These findings follow a conflicting disproportionality analysis published in JAMA Open Network on August 20, 2024, which used World Organization data and found evidence to support semaglutide may be linked to increased suicidality.^3,4 HCPLive spoke with the lead investigator of the post-hoc analysis, Thomas A. Wadden, PhD, from Perelman School of Medicine at the University of Pennsylvania, who explained the study published about 2 weeks ago used surveillance data which was not as controlled as the 4 randomized control trials the post-hoc analysis examined.

“…when you do careful assessments of people, and you can carefully characterize the population under those circumstances, there’s really no signal of suicidal ideation or depression or suicidal behavior,” Wadden said.

Surveillance data relies on people reporting adverse events to the US Food and Drug Administration (FDA) or the European Medicines Agency and does not take into consideration cause and effect. The upside to surveillance data is that investigators have access to a lot more participants than in a small, randomized control trial. Conversely, a limitation of using surveillance data is that it is hard to have a good measurement of suicidal ideation.

“Studies that are getting reports from general practitioners or from patients often can't discriminate between the degree of suicide,” Wadden said.

Suicidal ideation comes in 3 categories, stretching from passive ideation where you would like to go to bed and not wake up to serious suicidal ideation where you wish to die and have a plan to kill yourself. Thus, that is where randomized controlled trials come in use: they can determine a participant’s suicide degree.

However, Wadden said the post-hoc analysis was limited by not including people with active, ongoing major depression or serious suicidal ideation. The study excluded people who had major depression, bipolar disorder, schizophrenia, and severe anxiety. Due to this exclusion, the study cannot determine how safe semaglutide is for people with known mental health issues.

Wadden theorized possible reasons—mechanisms—for why semaglutide was not linked to increased depression or suicidal ideation risk. The research showed more patients on placebo than on semaglutide were likely to develop moderately severe or greater symptoms

“It looks like the medication, probably, by helping people lose weight is protecting them against negative mood,” Wadden said. “It's a very tiny difference, though. That's just a difference of [about] 1.3 percentage points, and that's why we don't think it's clinically meaningful to talk about it. But if there's any mechanism, it's probably the people losing weight are happier than the people who are not losing weight.”

References

1. ^{Wadden TA, Brown GK, Egebjerg C, 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. Published online September 03, 2024. doi:10.1001/jamainternmed.2024.4346}
2. ^{Derman, C. Semaglutide Not Linked to Suicidal Risks in Those Without Major Psychiatric Disorders. HCPLive. September 4, 2024. https://www.hcplive.com/view/semaglutide-not-linked-to-suicidal-risks-in-those-without-major-psychiatric-disorders. Accessed September 4, 2024.}
3. ^{Derman, C. Semaglutide Linked to Suicidal Ideation, New Study Reveals. HCPLive. August 23, 2024. https://www.hcplive.com/view/semaglutide-linked-to-suicidal-ideation-new-study-reveals. Accessed September 4, 2024.}
4. ^{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}