GLP-1 Agents and Suicide: Making Sense of 2024’s Mixed Data

In January, we reported on the FDA clearing GLP-1 receptor agonists of suicidality risk following a preliminary evaluation. In this report, we follow up on what has happened since.

Not long after the FDA wrapped its preliminary investigation of GLP-1 receptor agonists and suicidal thoughts or actions, the European Medicines Agency (EMA) followed suit with its own review. In April, the EMA said it also didn’t find a causal link.

This conclusion was largely based on two studies of patients on semaglutide (Ozempic, Rybelsus, Wegovy) that looked at patients with overweight or obesity and with type 2 diabetes. Both found a significantly lower risk of suicidal ideation among users compared with users of non-GLP-1 medications.

Despite both agencies’ reports early in the year, the topic sustained interest throughout 2024, with new analyses drawing conflicting conclusions.

Studies Show Different Findings

A few weeks after the EMA’s report was released, several case studies — similar to the reports that prompted the FDA’s and EMA’s investigations — were presented at the American Psychiatric Association annual meeting.

One instance involved a 42-year-old female patient who suddenly developed behavioral disruptions and protracted nihilistic delusion, then attempted to self-strangulate 3 weeks into semaglutide initiation.

“This is becoming such a popular medication and it has a lot of great effects,” case study author Shahan Syed, MD, of Bergen New Bridge Medical Center in Paramus, New Jersey, told MedPage Today at the conference. “It works on fat cells primarily, but it also works on muscles. And the brain is essentially all that. Would this be affecting the brain? We don’t know.”

Fast-forward to July, when a target trial emulation study led by Jingchuan Guo, MD, PhD, of the University of Florida College of Pharmacy in Gainesville, analyzed Medicare data from 2017 through 2020 and compared GLP-1 users with SGLT-2 inhibitor and DPP-4 inhibitor users. Guo’s group found that GLP-1 users didn’t have an increased risk for suicidal ideation and behaviors compared with people who used either of the two other diabetes drug classes.

By August, a disproportionality analysis based on World Health Organization reports from 2000 through 2023 found semaglutide users had 45% higher odds of suicidal ideation reports compared with all other drugs in the database. Liraglutide (Victoza, Saxenda) — another GLP-1 indicated for diabetes and weight management — did not have this same signal, according to Georgios Schoretsanitis, MD, PhD, of Zucker Hillside Hospital in Glen Oaks, New York, and co-authors.

Then, two JAMA Internal Medicine studies were published in September — this time with findings more congruent with the FDA’s review.

The first was an analysis of new users of a GLP-1 or SGLT2 inhibitor (primarily for diabetes) which found no difference in suicide death rates. There also were no differences between the two groups for new-onset depression and anxiety-related disorders, and slightly lower rates of the combined outcome of suicide death and nonfatal self-harm or self-harm alone in the GLP-1 group.

In the second — a post-hoc analysis of the STEP trials that supported semaglutide’s weight-loss indication — depression scores were lower at study end for patients on semaglutide versus placebo. Semaglutide-treated patients were also significantly less likely to shift to a more severe category of depression, reported Thomas Wadden, PhD, of the Center for Weight and Eating Disorders in Philadelphia, and colleagues.

In October, a retrospective cohort study helped assuage fears. Here, adolescents with obesity taking a GLP-1 had a 33% reduced risk for suicidal ideation or attempts over 1 year of follow-up compared with matched controls engaging in lifestyle interventions without GLP-1 therapy.

Why Are the Data Mixed?

Discrepancies could be due to differences in study design, population characteristics, and confounding factors such as underlying psychiatric conditions, Huilin Tang, MSc, of the University of Florida College of Pharmacy, told MedPage Today. But he said it’s “essential” to interpret all the findings from the year’s studies cautiously, and to keep in mind that the incidence of reported suicidality-related events was low.

Wadden previously noted that “it’s very difficult to isolate whether the [mental health] complications [in GLP-1 users] are associated with the patient’s obesity, with life stressors, with a personal or family history of psychiatric illness, or possibly with an adverse effect of a medication for weight management.”

Echoing this sentiment in an editorial, Roger McIntyre, MD, of the University of Toronto in Canada, wrote that patients prescribed a GLP-1 on-label “are differentially affected by underlying mental illness which provides potential explanation for observed reports of suicidality.”

Nonetheless, it’s prudent for GLP-1 prescribers and users “to remain vigilant” for suicidality, Tang said, and users — especially high-risk ones — should be monitored for mood changes. “Patients with a history of psychiatric disorders or those currently experiencing depressive symptoms might warrant closer monitoring, given their increased baseline risk,” he said.

Schoretsanitis agreed, saying that treatment “should be based on a careful evaluation of risks and benefits” including the possibility of suicidality risk. He also “categorically discourage[d]” off-label use without medical supervision.

Because of the GLP-1 popularity boom, Syed expects to see more of these cases. Even patients without a psychiatric history “should be evaluated once a week just to check in on their mood, their sleep, their appetite, and especially their anxiety,” he said.

Looking Ahead

While the year’s data overall don’t “strongly implicate GLP-1s,” Tang said that for healthcare providers, “a cautious approach is justified until more definitive evidence is available.” He said it’s crucial that healthcare providers engage in shared decision-making with patients and educate them on all possible side effects, including rare psychiatric symptoms.

Tang suggested future studies take the shape of three designs: target trial emulation studies; randomized controlled trials with psychiatric endpoints; or mechanistic studies exploring how GLP-1s might affect the central nervous system or mood, as they could uncover biological pathways and clarify potential causality.