Impaired lipid homeostasis and elevated lipid oxidation of erythrocyte membrane in adolescent depression

Adolescent depression is a globally concerned mental health issue, the pathophysiological mechanisms of which remain elusive. Membrane lipids play a crucial role in brain development and function, potentially serving as a crossroad for the abnormalities in neurotransmitters, neuroendocrine, inflammation, oxidative stress, and energy metabolism observed in depressed adolescents. The primary aim of this study was to investigate the erythrocyte membrane lipid profile in adolescent depression. A total of 2838 erythrocyte membrane lipids were detected and quantified in 81 adolescents with depression and 67 matched healthy adolescents using ultra-high performance liquid chromatography-mass spectrometry. Depressed adolescents exhibited significantly different membrane lipid characteristics compared to healthy controls. Specifically, the levels of cholesterol, sphingomyelins, and ceramides were increased, while ether lipids were decreased in patients. Moreover, the patients showed reduced polyunsaturated fatty acids and elevated lipophilic index in membrane, suggesting diminished membrane fluidity. The higher oxidized membrane lipids and plasma malondialdehyde were observed in adolescent depression, indicating the presence of oxidative stress. Importantly, membrane lipid damage was associated with more severe depressive symptoms and worse cognitive function in patients. In addition, reduced polyunsaturated fatty acids and membrane fluidity may be partly responsible for the blunted niacin skin flushing response found in depressed adolescents. In conclusion, our results reveal impaired erythrocyte membrane lipid homeostasis in adolescents with depression, which may implicate membrane dysfunction in the brain. These findings offer new insights into the underlying molecular mechanisms of adolescent depression, highlighting the potential of counteracting membrane damage as a promising avenue for future therapeutic interventions.