Hippocampal gray matter volume alterations in patients with first-episode and recurrent major depressive disorder and their associations with gene profiles

Recent studies indicate that patients with first-episode drug-naïve (FEDN) and recurrent major depressive disorder (R-MDD) exhibit distinct atrophy patterns in the hippocampal subregions along the proximal-distal axis. However, it remains unclear whether such differences occur along the long axis and how they may relate to specific genes. In the present study, we analyzed T1-weighted images from 421 patients (FEDN: n = 232; R-MDD: n = 189) and 544 normal controls (NC) as part of the REST-meta-MDD consortium. Additionally, transcriptome maps and structural Magnetic Resonance Imaging (MRI) data of six donated brains were obtained from the Allen Human Brain Atlas (AHBA). We first identified changes in gray matter volume (GMV) within the hippocampus of both FEDN and R-MDD patients and then integrated these findings with AHBA transcriptome data to investigate the genes associated with hippocampal GMV changes. Compared to NC, FEDN patients displayed reduced GMV in the left hippocampal tail, whereas R-MDD patients exhibited decreased GMV in the bilateral hippocampal body and increased GMV in the bilateral hippocampal tail. Further analysis revealed that expression levels of SYTL2 positively correlated with GMV changes in the hippocampus of FEDN patients, while SORCS3 and SLIT2 positively correlated with those in R-MDD. Our results suggest that GMV alterations in hippocampal subfields along the long axis differ between FEDN and R-MDD, reflecting progressive hippocampal deterioration with prolonged depression, potentially supported by the expression of specific genes. These findings offer valuable insights into the distinct neural and genetic mechanisms underlying FEDN and R-MDD, which may aid in the development of more targeted and effective treatment strategies for MDD subtypes.