A central role for the acid sphingomyelinase/ceramide system in neurogenesis and major depression

Major depressive disorder is a severe and chronic illness with high lifetime prevalence and a high incidence of suicide as the cause of death for patients with this diagnosis. Major depressive disorder is often treated with anti‐depressants. Although these drugs have been used for many years, their exact mode of action is still unknown. It has been suggested that many anti‐depressants act by increasing the concentrations of serotonergic transmitters in the synaptic space. However, recent studies have examined the effects of anti‐depressants on neurogenesis in the hippocampus, the restoration of hippocampal neuronal networks that may be affected by major depression, and the regulation of the hypothalamic–pituitary–adrenal axis by immature neurons in the hippocampus. Here, we present and discuss a novel hypothesis suggesting that these events are regulated by the concentrations of sphingolipids, in particular ceramide, in the hippocampus. These concepts suggest that the acid sphingomyelinase/ceramide system plays a central role in the pathogenesis of major depression and may be a novel target for anti‐depressants. image Major depressive disorder is a severe and chronic illness with high lifetime prevalence and high incidence of suicide. Major depression is caused in part by an imbalance between factors that positively and negatively control neurogenesis. Anti‐depressants inhibit the acid sphingomyelinase/ceramide system and thereby reduce the sum of negative factors restoring neurogenesis, neuronal survival, and improved mood.