Narrative review links ceramide elevations to major depressive disorder and suicidal vulnerability.

Major depressive disorder (MDD) and treatment-resistant depression (TRD) are biologically heterogeneous conditions with substantial suicide risk, yet current diagnostic frameworks lack validated biological markers for patient stratification. This narrative review examines the role of ceramides and lipid metabolism as immunometabolic drivers and potential biomarkers in MDD, TRD, and suicidal vulnerability. We integrate evidence from lipidomic, neuroinflammatory, and translational studies to characterize how ceramides, generated through de novo 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.