Retinal Cytoarchitectural Alterations Across the Psychosis Spectrum and Their Correlates with Cognition: A UK Biobank Nested Case-Control Study

Retinal structure may serve as a biomarker for psychosis-spectrum disorders (PSD) and cognition, but larger, well-controlled and detailed studies are needed. This study investigates retinal thickness differences and their association with cognition in PSD (including schizophrenia, bipolar disorder, and major depression with psychosis) compared to age-, sex-matched healthy controls (HC). In this nested case-control study using the UK Biobank data, 476 participants underwent macular optical coherence tomography (OCT). Repeated-measures ANCOVA assessed retinal thickness across two measures (left/right eyes) and two groups (PSD/HC). Comprehensive analyses were conducted, accounting for various sociodemographic (ethnicity, area-level deprivation, etc); ocular (visual acuity, intraocular pressure, etc); and health (blood pressure, body mass index) covariates, as well as excluding individuals with cardiometabolic conditions. Layers were evaluated to determine their relationship with cognition. Thinner maculae ( F =23.02, η²p=.05, p <.001), ganglion cell-inner plexiform ( F =6.42, η²p=.01, p =.043) and photoreceptor layers ( F =35.31, η²p=.07, p <.001) were identified in PSD. The macular nerve fiber, inner nuclear, and retinal pigment epithelium layers appeared unaffected. Furthermore, smaller photoreceptor layer thickness was associated with poorer prospective memory performance (ß=0.12, B=2.15, 95% CI [0.39, 3.92], p =.017). The schizophrenia ( F =26.84, η²p=.07, p <.001) and bipolar disorder ( F =16.60, η²p=.05, p =.006) groups demonstrated the greatest as well as overlapping alterations in the photoreceptor layers. Individuals with PSD exhibit synaptic, ganglion-cell, and photoreceptor structural alterations with ocular and health-related factors —particularly cardiometabolic disorders— likely contributing to these changes. Changes in photoreceptor morphology in PSD could be related to neurobiological mechanisms associated with visual processing and memory deficits.