Optic disc morphometrics as a potential ocular biomarker for depression: evidence from two cross-sectional cohort studies

Depression, which is increasingly prevalent among older adults, has traditionally been diagnosed through symptom-based questionnaires. However, emerging evidence suggests that retinal changes could serve as objective biomarkers for depression. In this study, we investigated the optic disc signature of depression by leveraging automated fundus morphometrics (deep learning segmentation) and Olink-based plasma proteome profiling to explore potential mechanistic pathways. A total of 412 participants from two independent cohorts, the UK Biobank and the Guangdong Ophthalmic-Psychological Health Study (GD-OPHS), were included in the analysis. Our findings indicate that individuals with depression exhibited increased roundness of the optic disc (UK Biobank: OR = 1.12, 95% CI = 1.01–1.25; GD-OPHS: OR = 1.16, 95% CI = 1.02–1.32) and a larger optic disc tilt angle (UK Biobank: OR = 2.83, 95% CI = 1.61–4.96; GD-OPHS: OR = 1.81, 95% CI = 1.02–3.21). Importantly, optic disc roundness correlated with the expression of two depression-related proteins, LRRN1 (p = 0.010) and PRL (p = 0.022). Both LRRN1 and PRL are enriched in the retina, as well as in key brain regions involved in emotional regulation, including the cerebral cortex, thalamus, and hippocampus. Given the strong connections between the retina and the central nervous system, our results suggest that optic disc morphology may serve as an objective, non-invasive biomarker for depression.