Unveiling Chiral Amino Acid Alterations and Glycine Dysregulation in Late-Life Depression through Targeted Metabolomics

Mingxia LiuWeigang PanJing HeSihai LingYi HeJian YangPeixian MaoZuoli Sun^*

• Capital Medical University, Beijing, China

Late-life depression (LLD) is a major depressive disorder that is highly prevalent among older people, and there are currently no validated biomarkers for the diagnosis and treatment of LLD. Although dysregulated amino acid metabolism has been increasingly implicated in neuropsychiatric disorders, including LLD, most existing studies overlook the chiral nature of amino acids, potentially leading to inaccurate or incomplete findings. To address this gap, this study aimed to precisely characterize the serum chiral amino acid profiles in patients with LLD and identify potential biomarkers. Using liquid chromatography-tandem mass spectrometry combined with a chiral derivatization technique, the serum levels of 34 amino acids were analyzed in 53 LLD patients and 37 healthy controls (HCs). Significant alterations in both D- and L-enantiomers were observed, including reduced levels of D-methionine, D-glutamic acid, D-threonine, and L-threonine, alongside elevated glycine levels in LLD compared to HCs. The combination of D-methionine and glycine demonstrated moderate discriminatory power for distinguishing LLD from HCs, with an area under the curve of 0.71. Notably, glycine levels were significantly lower in antidepressant treatment responders than in non-responders. Additionally, D- and L-glutamic acid levels were differentially associated with specific cognitive function indicators. These findings underscore the importance of accounting for amino acid chirality in biomarker research and highlight chiral amino acids as promising candidates for the diagnosis of LLD and the prediction of treatment response.