Prescription Sequence Symmetry Analysis of Glucagon‐Like Peptide‐1 Receptor Agonists and Neuropsychiatric Conditions

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are increasingly prescribed for type 2 diabetes and weight management. However, conflicting evidence from preclinical, clinical, and pharmacovigilance studies suggests potential neuropsychiatric effects. This study examined associations between GLP-1RA use and initiation of a range of neuropsychiatric medications using real-world prescription data. A Prescription Sequence Symmetry Analysis was conducted using Australia's Pharmaceutical Benefits Scheme 10% random sample between July 1, 2013 and December 31, 2024. Individuals with an incident dispensing of both a GLP-1RA and a neuropsychiatric medication were included. Outcomes comprised antidepressants, medication for substance use disorder (SUD), antipsychotics, psychostimulants, antidementia medications, antiparkinsonian medications, antiepileptics, and antimigraine agents. Adjusted sequence ratios (aSRs) with 95% confidence intervals (CIs) were calculated using a one-year exposure window, with sensitivity analyses varying various time windows. Among 2,033 individuals, semaglutide was the most common GLP-1RA (50.6%), followed by exenatide (27.5%) and dulaglutide (21.9%). GLP-1RA initiation was inversely associated with initiation of antidepressants (aSR: 0.85; 95% CI: 0.76-0.94) and medications for SUD (aSR: 0.70; 95% CI: 0.51-0.88). No significant associations were observed for other neuropsychiatric outcomes. GLP-1RA use was inversely associated with subsequent initiation of antidepressants and medications for SUD, while no associations were identified for other neuropsychiatric marker medications. These findings highlight the need for further studies to clarify the nature and magnitude of these potential neuropsychiatric associations with GLP-1RAs.