The mechanisms of action of most antidepressants are unclear. A study in Nature Medicine now shows that therapeutic concentrations of the antidepressants amitriptyline and fluoxetine reduced the activity of acid sphingomyelinase (ASM), an enzyme that releases ceramide from sphingomyelin, in both cultured neurons and mouse hippocampi. Reducing ceramide levels in the brain had antidepressant effects in mouse models of depression, suggesting that the ASM–ceramide system may be a useful target for new antidepressants.