Ceramides and neuroinflammation as immunometabolic drivers and biomarkers of major depressive disorder, treatment-resistant depression, and suicidal vulnerability

synthesis, sphingomyelinase-mediated pathways, and salvage mechanisms, participate in microglial priming, blood-brain barrier compromise, synaptic dysfunction, and regulated cell death. Ceramide accumulation, modulated by HPA axis dysregulation, adiposity, and comorbid metabolic conditions, intersects with tryptophan-kynurenine pathway alterations and mitochondrial bioenergetic deficits, converging on a multi-level immunometabolic framework relevant to depressive and treatment-resistant phenotypes. Circulating ceramide species, particularly C16-C24:1, show consistent elevations in MDD and correlate with symptom severity, antidepressant exposure, and sex-specific patterns, while indirect evidence links lipid dysregulation to suicidal behavior. Acid sphingomyelinase inhibition by functional antidepressants highlights a pharmacologically relevant axis. Current evidence is constrained by cross-sectional designs, small samples, and heterogeneous platforms. Longitudinal, multi-omic studies with harmonized protocols are needed to determine whether ceramide profiles can inform risk stratification and personalized interventions in precision psychiatry.