Association between peripheral inflammation and free-water imaging in Major Depressive Disorder before and after ketamine treatment – A pilot study

Alterations in the peripheral inflammatory profile and white matter (WM) deterioration are frequent in Major Depressive Disorder (MDD). The present study applies free-water imaging to investigate the relationship between altered peripheral inflammation and WM microstructure and their predictive value in determining response to ketamine treatment in MDD. Ten individuals with MDD underwent diffusion-weighted magnetic resonance imaging and a blood-draw before and 24 h after ketamine infusion. We utilized MANCOVAs and ANCOVAs to compare tissue-specific fractional anisotropy (FAT) and free-water (FW) of the forceps and cingulum, and the ratio of pro-inflammatory interleukin(IL)-8/anti-inflammatory IL-10 between individuals with MDD and 15 healthy controls at baseline. Next, we compared all baseline measures between ketamine responders (6) and non-responders (4) and analyzed changes in imaging and blood data after ketamine infusion. The MDD group exhibited an increased IL-8/IL-10 ratio compared to controls at baseline (p = .040), which positively correlated with average FW across regions of interest (p = .013). Ketamine responders demonstrated higher baseline FAT in the left cingulum than non-responders (p = .023). Ketamine infusion did not influence WM microstructure but decreased the IL-8/IL-10 ratio (p = .043). The small sample size and short follow-up period limit the conclusion regarding the longer-term effects of ketamine in MDD. This pilot study provides evidence for the role of inflammation in MDD by illustrating an association between peripheral inflammation and WM microstructure. Additionally, we demonstrate that free-water diffusion-weighted imaging might be a valuable tool to determine which individuals with MDD benefit from the anti-inflammatory mediated effects of ketamine treatment. •Inflammatory imbalance in depression with increased interleukin (IL)-8/IL-10 ratio•Correlation of peripheral inflammation with free-water across regions of interest•White matter microstructure in cingulum predicts ketamine response•Ketamine decreases IL-8/IL-10 ratio 24 h after treatment