GLP-1 RAs Reduce Suicidal Behavior in Adolescents

Glucagon-like peptide 1 receptor agonists (GLP-1 RAs) given to adolescents with obesity was associated with a one-third decreased risk for suicidal ideation and suicide attempts compared with lifestyle intervention alone, a large international retrospective study found.

A study published on October 14, 2024, in JAMA Pediatrics suggested that GLP-1 RAs such as semaglutide, liraglutide, and tirzepatide, which are widely used to treat type 2 diabetes (T2D), have a favorable psychiatric safety profile and open up potential avenues for prospective studies of psychiatric outcomes in adolescents with obesity.

Investigators Liya Kerem, MD, MSc, and Joshua Stokar, MD, of Hadassah University Medical Center in Jerusalem, Israel, reported that the reduced risk in GLP-1 RA recipients was maintained up to 3 years’ follow-up compared with propensity score–matched controls treated with behavioral interventions alone.

“These findings support the notion that childhood obesity does not result from lack of willpower and shed light on underlying mechanisms that can be targeted by pharmacotherapy.” Kerem and Stokar wrote.

Other research has suggested these agents have neurobiologic effects unrelated to weight loss that positively affect mood and mental health.

Study Details

The analysis included data from December 2019 to June 2024, drawn from 120 international healthcare organizations, mainly in the United States. A total of 4052 racially and ethnically diverse adolescents with obesity (aged 12-18 years [mean age, about 15.5 years]) being treated with an anti-obesity intervention were identified for the GLP-1 RA cohort and 50,112 for the control cohort. The arms were balanced for baseline demographic characteristics, psychiatric medications and comorbidities, and diagnoses associated with socioeconomic status and healthcare access.

Propensity score matching (PSM) resulted in 3456 participants in each of two balanced cohorts.

Before PSM, intervention patients were older (mean age, 15.5 vs 14.7 years), were more likely to be female (59% vs 49%), and had a higher body mass index (41.9 vs 33.8). They also had a higher prevalence of diabetes (40% vs 4%) and treatment with antidiabetic medications.

GLP-1 RA recipients also had a history of psychiatric diagnoses (17% vs 9% for mood disorders) and psychiatric medications (18% vs 7% for antidepressants). Previous use of non–GLP-1 RA anti-obesity medications was uncommon in the cohort overall, although more common in the GLP-1 RA cohort (2.5% vs 0.2% for phentermine).

Prescription of GLP-1 RA was associated with a 33% reduced risk for suicidal ideation or attempts over 12 months of follow-up: 1.45% vs 2.26% (hazard ratio [HR], 0.67; 95% CI, 0.47-0.95; P = .02). It was also associated with a higher rate of gastrointestinal symptoms: 6.9% vs 5.4% (HR, 1.41; 95% CI, 1.12-1.78; P = .003). There was no difference in rates of upper respiratory tract infections (URTIs), although some research suggests these agents reduce URTIs.

Mechanisms

The etiology of childhood obesity is complex and multifactorial, the authors wrote, and genetic predisposition to adiposity, an obesogenic environment, and a sedentary lifestyle synergistically contribute to its development. Variants in genes active in the hypothalamic appetite-regulation neurocircuitry appear to be associated with the development of childhood and adolescent obesity.

The authors noted that adolescence carries an increased risk for psychiatric disorders and suicidal ideation. “The amelioration of obesity could indirectly improve these psychiatric comorbidities,” they wrote. In addition, preclinical studies suggested that GLP-1 RA may improve depression-related neuropathology, including neuroinflammation and neurotransmitter imbalance, and may promote neurogenesis.

A recent meta-analysis found that adults withT2D treated with GLP-1 RA showed significant reduction in depression scale scores compared with those treated with non-GLP-1 RA antidiabetic medications.

Commenting on the study but not involved in it, psychiatrist Robert H. Dicker, MD, associate director of child and adolescent psychiatry at Northwell Zucker Hillside Hospital in Glen Oaks, New York, cautioned that these are preliminary data limited by a retrospective review, not a prospective double-blind, placebo-controlled study.

“The mechanism is unknown — is it a direct effect on weight loss with an improvement of quality of life, more positive feedback by the community, enhanced ability to exercise, and a decrease in depressive symptoms?” he asked.

Dicker suggested an alternative hypothesis: Does the GLP-1 RA have a direct effect on neurotransmitters and inflammation and, thus, an impact on mood, emotional regulation, impulse control, and suicide?

“To further answer these questions, prospective studies must be conducted. It is far too early to conclude that these medications are effective in treating mood disorders in our youth,” Dicker said. “But it is promising that these treatments do not appear to increase suicidal ideas and behavior.”

Adding another outsider’s perspective on the study, Suzanne E. Cuda, MD, MFOMA, FAAP, a pediatrician who treats childhood obesity in San Antonio, said that while there was no risk for increased psychiatric disease and a suggestion that GLP-1 RAs may reduce suicidal ideation or attempts, “I don’t think this translates to a treatment for depression in adolescents. Nor does this study indicate there could be a decrease in depression due specifically to the use of GLP1Rs. If the results in this study are replicated, however, it would be reassuring to know that adolescents would not be at risk for an increase in suicidal ideation or attempts.”

This study had no external funding. Kerem reported receiving personal fees from Novo Nordisk for lectures on childhood obesity outside of the submitted work. No other disclosures were reported. Dicker and Cuda had no competing interests relevant to their comments.

Diana Swift is a medical journalist based in Toronto, Ontario, Canada.