GLP-1 RAs reduce depression, substance use in young patients with obesity, MASLD

In paediatric patients with obesity and metabolic dysfunction-associated steatotic liver disease (MASLD), treatment with GLP-1 receptor agonists (RAs) results in a decrease in depression and substance use, as shown in a study presented at ESPGHAN 2025.

“GLP-1 RAs may offer mental health benefits in patients with obesity and MASLD, mainly by reducing the odds of depression, nicotine dependence, and vaping,” said lead author Dr Arleen Delgado, Woodhull Medical and Mental Health Center in Brooklyn, New York, US.

This benefit is driven by overlapping pathways involved in addiction and impulsivity “that can be attributed to antioxidative and anti-inflammatory properties,” she added.

Using data from the TriNetX platform, Delgado and her team included 206,418 patients aged 12‒21 years with obesity and a MASLD diagnosis between January 2014 and 2024 in this retrospective cohort study. They assessed the impact of GLP-1 RAs, such as semaglutide, liraglutide, dulaglutide, tirzepatide, and exenatide, on the likelihood of developing mental health disorders.

Odds ratios (ORs) and 95 percent confidence intervals (CIs) were calculated using logistic regression both in raw and propensity score-matched cohorts. Statistical significance was set at p<0.05.

Mental health benefits

Patients treated with GLP-1 RAs were less likely to develop depression (OR, 0.70, 95 percent CI, 0.52‒0.94; p<0.01) or to engage in nicotine (OR, 0.61, 95 percent CI, 0.39‒0.95; p=0.029) and vaping use (OR, 0.58, 95 percent CI, 0.29‒0.91; p<0.01). The use of GLP-1 RAs also helped lower the likelihood of suicidal ideations (OR, 0.54, 95 percent CI, 0.29‒1.00; p=0.047). [ESPGHAN 2025, abstract N-OP031]

Likewise, the odds for drug (OR, 0.66, 95 percent CI, 0.35‒1.24; p=0.198) and alcohol use (OR, 0.52, 95 percent CI, 0.24‒1.12; p=0.964) were reduced, but these did not reach statistical significance.

In contrast, treatment with GLP-1 RAs appeared to have no significant effects on anxiety (OR, 0.78, 95 percent CI, 0.57‒1.06; p=0.12), attention-deficit/hyperactivity disorder (OR, 0.98, 95 percent CI, 0.40‒2.36; p=0.964), conduct (OR, 0.99, 95 percent CI, 0.41‒2.38; p=0.984), and eating disorder (OR, 1.10, 95 percent CI, 0.51‒2.35; p=0.799).

“What we saw that was significant in this population was improvements in depression … suicidal ideation, and … vaping, as well as nicotine dependence,” said study presenter and co-author Dr Thomas Wallach, SUNY Downstate Health Sciences University, Brooklyn, New York, US.

“All these things tended to trend positively with the exception of eating disorders, which is probably unsurprising, given that one of the side effects of this medication would qualify you for a diagnosis of an eating disorder in many patients,” he added.

Mechanisms

Delgado and Wallach, together with their colleagues, proposed some theories to explain the benefits of using GLP-1 RAs on mental health. These include inflammation reduction, neurotransmitter effects, and cultural or societal effects.

GLP-1 RAs reduce inflammatory markers associated with depression and may modulate dopamine and serotonin pathways in brain reward centres. These drugs also influence circuits that are responsible for mood regulation, according to the authors.

In addition, weight loss following the use of GLP-1 RAs may improve body image and self-esteem. Patients also achieve a sense of agency associated with effective therapy.

Being on these medications, “you will end up having improvements in neuromodulatory effects for dopamine and serotonin pathways,” Wallach said. “You can have some sign that there’s antidepressant effects, there’s increasing linkage of inflammation as a causal mediator of depression and anxiety.”

“Additional research is necessary,” Delgado said.