Estimating Accelerated Retinal Decline in Mental Health Disorders Through Normative Modeling

Background and hypothesis: Several studies have found that retinal tissue is thinner in people with mental health disorders than in healthy controls (HC). However, most research has examined group-level differences and has therefore inadequately accounted for normative biological heterogeneity. A focus on single disorders has also made transdiagnostic comparisons challenging. We used normative modeling to estimate age-related decline of the human retina (and its expected variation) and compared it to the decline seen in schizophrenia (SZ), bipolar disorder (BD), and major depressive disorder (MDD). We hypothesized accelerated retinal decline in mental health disorders compared to controls, with SZ being most affected, followed by BD, then MDD. Study design: Using UK Biobank data, we estimated age-related retinal decline (age range: 40-70) in HC (n = 51 225) for total macular thickness (including coronal subfields) and its 8 segmented sublayers. We then compared the decline in SZ (n = 170), BD (n = 263), and MDD (n = 95) to the normative decline in HC. Adjustments were made for known confounding variables. Study results: For HC, the pattern of estimated age-related decline for retinal thickness was curve-like and generally more pronounced in males compared to females. Individuals with a mental health disorder showed more pronounced retinal thinning; this effect was greatest in SZ and disorder-specific macular subfields. There was also an enrichment of individuals with extremely low (infranormal) values in the patient group. Conclusion: Our findings suggest that major mental health disorders, particularly SZ, involve accelerated retinal thinning, detectable with normative modeling.