Retrobulbar Hemodynamic Alterations in Major Depressive Disorder: A Case- Control Color Doppler Study

<title>Abstract</title> <p> <bold>Introduction</bold> Major depressive disorder (MDD) has increasingly been conceptualized as a multisystem disorder involving autonomic, inflammatory, endothelial, and microvascular pathways. The retina and retrobulbar circulation provide an accessible window into neurovascular biology, but feeding-vessel hemodynamics in MDD remain insufficiently characterized. To test the hypothesis that MDD is associated with vessel-specific retrobulbar hemodynamic dysregulation, particularly reduced downstream retinal and posterior ciliary perfusion and increased vascular impedance. <bold>Methods</bold> This case-control study was conducted at Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran, during 2024–2025. Twenty adults with DSM-5 MDD and 30 healthy controls underwent ophthalmic examination and orbital color Doppler sonography. Peak systolic velocity (PSV), end-diastolic velocity (EDV), resistive index (RI), and pulsatility index (PI) were assessed in the ophthalmic artery (OA), central retinal artery (CRA), and posterior ciliary artery (PCA). The primary analysis used multivariate analysis of covariance adjusted for age, followed by age-adjusted univariable models with Bonferroni correction. <bold>Results</bold> The MDD group had higher HAM-D scores and was older than controls; intraocular pressure and subfoveal choroidal thickness did not differ significantly. Age-adjusted multivariate analysis demonstrated a strong overall group effect on the retrobulbar Doppler profile (Pillai trace = 0.954, F(12,36) = 62.06, p &lt; 0.001). Compared with controls, MDD patients showed higher OA-PSV and OA-RI, lower CRA-PSV and CRA-EDV, higher CRA-PI, lower PCA-PSV and PCA-EDV, and higher PCA-RI after Bonferroni correction. Recalculated CRA-RI did not differ significantly between groups. Exploratory severity analyses suggested associations between HAM-D score and PCA-RI/CRA-PI, but these did not survive false-discovery-rate correction. <bold>Conclusions</bold> MDD was associated with a vessel-specific retrobulbar hemodynamic phenotype, dominated by reduced retinal and posterior ciliary flow velocities and increased posterior ciliary resistance. These findings support the microvascular/neurovascular framework of depression, but they should be interpreted as hypothesis-generating pending larger, age-matched, multimodal, and longitudinal validation. </p>