Abstract BACKGROUND: Depressive disorders (DD) are highly prevalent in patients with diabetic neuropathy (DN), yet a little is known about how commonly used neuropathic agents, duloxetine and gabapentin, differentially influence psychiatric outcomes in this population. MATERIALS AND METHODS: We conducted a retrospective cohort analysis using the TriNetX electronic health record network containing patient data from more than 69 healthcare organizations, version v5.0, between January 2000 and December 2025. After propensity score matching, patients treated for diabetic neuropathy were grouped into balanced cohorts of 18,674 gabapentin-treated patients and 16,223 duloxetine-treated patients. The primary outcome was new-onset DD within 5 years following initiation of treatment. Risk estimates and survival analyses compared cohorts. RESULTS: Patients treated with duloxetine had a significantly higher 5-year risk of developing DD than those treated with gabapentin (16.3% vs. 14.8%; risk ratio 1.099, 95% confidence interval CI: 1.046–1.154). Kaplan–Meier analysis demonstrated a lower survival probability free from DD in the duloxetine group (83.7% vs. 85.2%), with a hazard ratio of 1.318 (95% CI 1.250–1.391, P < 0.001). CONCLUSION: In this propensity score-matched real-world cohort, duloxetine was associated with a significantly higher, albeit small absolute risk of incident DD compared with gabapentin. These findings suggest a correlational association with the use of duloxetine and psychiatric risk in this specific patient population. This highlights possible consideration of psychiatric outcomes when treatments are selected for DN and also supports the need for future prospective studies to confirm causality and further evaluate the psychiatric effects of therapies for neuropathic pain.
Zerefos et al. (Wed,) studied this question.