Retinal electrophysiology as a translational biomarker in mood disorders: a systematic review and meta-analysis

Background: Mood disorders are prevalent psychiatric conditions associated with substantial disability and diagnostic challenges, particularly in distinguishing major depressive disorder (MDD) from bipolar disorder (BD) [1; 2]. The identification of objective biomarkers reflecting central nervous system dysfunction in mood disorder is therefore a major challenge to improve early and accurate diagnosis. The retina, sharing structural and neurochemical properties with the brain, is a promising candidate [3]. Electroretinography (ERG) is a non-invasive technique that enables the assessment of retinal electrophysiological responses and may offer translational insights into neurobiological alterations in mood disorders.

Aims: This study aimed to systematically review ERG findings in mood disorders and to quantitatively synthesise available evidence to determine whether consistent retinal alterations can be identified.

Methods: A systematic search of PubMed, Web of Science, Embase and APA PsycINFO databases was conducted up to 25 November 2025 (PROSPERO ID: 1234381). Studies assessing ERG outcomes in individuals with mood disorders or genetically high-risk populations were included. Two reviewers independently screened studies and extracted data, with discrepancies resolved by consensus. Methodological quality was assessed using a modified Newcastle–Ottawa Scale. Quantitative synthesis was performed for full-field ERG parameters in MDD without reported specifiers using random-effects models with restricted maximum likelihood (REML). Effect sizes were expressed as standardised mean differences with 95% confidence intervals, and heterogeneity was assessed using the I² statistic. Sensitivity analyses were conducted using externally studentized residuals (|rstudent| > 2) to explore the influence of individual studies.

Results: Thirty-two studies were included in the systematic review and five in the meta-analysis. Across studies, mood disorders were frequently associated with reduced ERG amplitudes and prolonged implicit times. Meta-analysis revealed a significant prolongation of b-wave implicit time under mixed scotopic conditions in MDD (g = 0.23 [0.00 to 0.46]), while no significant differences were observed for other parameters in primary analyses. Sensitivity analyses indicated that some results were influenced by individual studies. Several studies also reported high diagnostic performance of ERG-based measures, with elevated sensitivity, specificity and area under the curve values in distinguishing MDD patients from controls. In unipolar seasonal affective disorder, retinal abnormalities appeared state-dependent, with reduced scotopic sensitivity during winter only. Studies in BD suggested mood-state-dependent alterations, with some parameters demonstrating high classification accuracy. In genetically high-risk offspring, similar b-wave alterations were observed in a subset of individuals and were often associated with subclinical and cognitive features.

Conclusions: ERG alterations are observed across mood disorders and may reflect disruptions in shared neurobiological pathways, particularly involving dopaminergic and circadian systems. Some alterations appear disorder- or state-dependent, supporting their potential relevance for differential diagnosis. As a non-invasive and objective measure, ERG therefore represents a promising translational biomarker for early detection, differential diagnosis and stratification of mood disorders. However, the available evidence remains limited and heterogeneous, highlighting the need for larger, standardised and longitudinal studies to determine its clinical utility.

References

1. GBD 2019 Mental Disorders Collaborators. Global, regional, and national burden of 12 mental disorders in 204 countries and territories, 1990–2019: a systematic analysis for the Global Burden of Disease Study 2019. Lancet Psychiatry. 2022;9:137 50.
2. McIntyre R, Zimmerman M, Goldberg J, First M. Differential Diagnosis of Major Depressive Disorder Versus Bipolar Disorder: Current Status and Best Clinical Practices. The journal of clinical psychiatry. 2019.
3. London A, Benhar I, Schwartz M. The retina as a window to the brain-from eye research to CNS disorders. Nat Rev Neurol. 2013;9(1):44 53. doi:10.1038/nrneurol.2012.227