Abstract:
Background: Glucagon-like peptide-1 (GLP-1) receptor agonists are seen as a first-line treatment for Type II Diabetes Mellitus (T2DM).1 However, multiple recent randomized controlled trials have shown that GLP-1 agonists are also effective for weight loss and metabolic control.2 Consequently, there has been a spike in the prescription of GLP-1 agonists for weight management rather than solely for diabetes. Despite its growing popularity, patients on GLP-1 agonists have voiced concerns of mood changes, anxiety, and depressive symptoms, suggesting possible psychiatric effects that may be underreported in clinical settings.3 Emerging research suggests a potential association between GLP-1 agonists and adverse psychiatric events.4 However, data remains mixed and limited. This study investigates the relationship between GLP-1 agonists and incidence of depression diagnosis in patients with obesity and without diabetes prescribed GLP-1 agonists for weight loss. Given the well-established bidirectional link between depression and obesity, it is crucial to further explore whether the use of these medications can manifest psychiatric side effects in this patient population.
Methods: The TriNetX database was queried for adult patients (ages 18-50) with BMI > 30 kg/m2 who were prescribed semaglutide (RxNorm 1991302), tirzepatide (RxNorm 2601723), or liraglutide (RxNorm 475968) for at least 6 months. Patients with a pre-existing diagnosis of depressive disorders, history of diabetes mellitus, or a hemoglobin A1C > 6.5% were excluded. The primary outcome of interest is a new diagnosis of depressive disorder at least one month following the first prescribed GLP-1 agonist dose. A diagnosis was identified via the ICD codes F32 (Major Depressive Disorder, Single) and F33 (Major Depressive Disorder, Recurrent).
Results: 100,386 patients with obesity without diabetes were included. Incidence of a depression diagnosis was significantly higher in patients prescribed with a GLP-1 agonist compared to patients not prescribed a GLP-1 agonist (29.89% vs. 18.9%, p<0.001). Elevated risks for a depression diagnosis was consistent across stratified age groups, with the highest risk observed in young adults at ages 18-24 (RR 1.52, 95% CI 1.44-1.59) and ages 25-34 (RR 1.52, 95% CI 1.48-1.56) compared to adults ages 45-50 (RR 1.37, 95% CI 1.34-1.40). When stratified by type of GLP-1 agonist, liraglutide demonstrated a higher risk of depression diagnosis (RR 1.63, 95% CI 1.57-1.69) compared to semaglutide (RR 1.58, 95% CI 1.55-1.61) and tirzepatide (RR 1.57, 95% CI 1.52-1.63).
Conclusion: These findings suggest that GLP-1 agonist usage in patients with obesity without diabetes is associated with a greater risk of depression diagnosis. The risk of depression remains generally consistent across stratified age groups and medication types. However, the strength of the association is particularly notable amongst young adults and liraglutide users. While the cause of increased depression risk remains unclear, these findings may support a need for psychiatric monitoring when introducing GLP-1 agonists to this patient population. Continued investigation on other psychiatric outcomes may provide further insight on potential neuropsychiatric effects of GLP-1 agonists.
