The early developmental roots of retinal layer thinning in adult patients with schizophrenia and bipolar or depressive disorder: Retina imaging in genetically high-risk children and adolescents

Background: Thinning of the macular ganglion cell inner plexiform layer (mGCL-IPL) of the retina has been consistently found in adults with schizophrenia (SZ), bipolar disorder (BP), and major depressive disorder (MDD). A possible developmental etiology for these disorders underscores the question of whether these retinal changes occur early in development rather than later in disease. This study provides, for the first time in psychiatry, an optical coherence tomography (OCT) examination of the retinal cytoarchitecture in genetically high-risk children and adolescents (GHRs).Methods: A total of 197 participants were examined with OCT: 70 unrelated adult patients with SZ, BP, or MDD compared to 53 controls, and 47 GHR children aged 6-17 years compared to 27 controls assessed with the same laboratory methods. Mean mGCL-IPL segments and four peripapillary retinal nerve fiber layer (pRNFL) quadrants were assessed by OCT. Groups were compared using mixed-effects regression models adjusted for age and sex. Results: We first confirmed in our laboratory that adult patients showed significant thinning of the mGCL-IPL compared to controls (β = -3.80 µm [95% CI: -7.00, -0.60], effect size of 0.42 [95% CI: 0.06, 0.78]), consistent with previous findings. Similarly, GHR children showed significant mGCL-IPL thinning (β = -7.50 µm [95% CI: -12.67, -2.34, effect size of 0.67 [95% CI: 0.18, 1.15]).Conclusions: The findings in the GHR children support an early developmental origin of the retinal mGCL-IPL thinning in adult patients and a potential trait-level endophenotype reflecting childhood neurodevelopmental vulnerability and a likely tool for early detection.