Introduction: Glucagon-like peptide-1 receptor agonists (GLP-1 RA) are widely utilized for diabetes and weight loss. Previous literature has shown a possible association to GLP-1 RA use and neuropsychiatric conditions resulting in warnings contained in package labeling.

Research Question or Hypothesis: Is there an association between GLP-1 RA use and depression?

Study Design: Retrospective cohort study

Methods: Data was obtained from national administrative data from the VA Corporate Data Warehouse via the VA Informatics and Computing Infrastructure. Depression diagnosis and comorbidities were identified using ICD codes. Prescription information including medication counts were obtained from outpatient pharmacy data. The primary outcome was incident depression, defined as a new diagnosis of depression or antidepressant prescription within 1 year following index initiation of a GLP-1RA, SGLT-2i or DPP-4i. Multivariable log binomial regression was used to estimate the relative risk of incident depression between GLP-1RA and DPP-4i exposure, while adjusting for potential confounders. Multiple sensitivity analyses were performed including stratified analyses, analysis of a secondary outcome measure and use of an alternative comparator group.

Results: The primary outcome of incident depression diagnosis or antidepressant prescription occurred in 7.7% (n= 2,263) of patients who initiated a GLP-1RA and 6.3% (n= 6,602) of patients who initiated a DPP-4i.  The corresponding unadjusted relative risk of 1.24 (95% CI: 1.18 – 1.29) indicated a significantly increased risk for incident depression following initiation of a GLP-1RA, relative to a DPP-4i. However, this relationship did not persist after adjustment for confounding factors including patient demographics, comorbid medical and psychiatric disorders, and prior medication exposure. After adjustment, the relative risk was 1.02 (95% CI: 0.97 – 1.07), thus failing to demonstrate a significant increase in risk for incident depression following GLP-1RA initiation, relative to a comparable therapeutic alternative.

Conclusion: This retrospective cohort study did not observe a significant increased risk for incident depression following GLP-1RA initiation.