Neuroprotection vs. Neurotoxicity: The Dual Impact of Brain Lipids in Depression

Growing neurochemical evidence highlights cerebral lipid dysregulation as a key factor in the pathophysiology of major depressive disorder (MDD). This review systematically explores the dual roles of lipid species in both normal behavioral regulation and MDD development. By critically examining the recent literature, we classify these lipid species into two functional categories based on their functional neuroactivity: (1) neuroprotective lipids (sphingomyelin, cholesterol, cardiolipin, sphingosine, phosphatidic acid, and phosphatidylserine), which exert neuroprotective effects by modulating membrane fluidity and supporting synaptic vesicle trafficking; and (2) neurotoxic lipids (ceramides, phosphatidylinositol, phosphocholine, and phosphatidylethanolamine), which promote apoptotic signaling cascades and disrupt mitochondrial bioenergetics. An unresolved but critical question pertains to the maintenance of homeostatic equilibrium between these opposing lipid classes. This balance is essential, given their significant impact on membrane protein localization and function, monoaminergic neurotransmitter metabolism, energy homeostasis, and redox balance in neural circuits involved in mood regulation. This emerging framework positions cerebral lipidomics as a promising avenue for identifying novel therapeutic targets and developing biomarker-based diagnostic approaches for MDD treatment.