Editors' ChoiceDepression

A Fat Chance for Antidepressants

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Science Translational Medicine  14 Aug 2013:
Vol. 5, Issue 198, pp. 198ec133
DOI: 10.1126/scitranslmed.3007181

Antidepressants are used to manage a variety of psychiatric conditions that range from major depression and mood disorders to chronic pain disorders. However, the mechanisms that mediate their effects are largely unknown. In a new study, Gulbins and colleagues present evidence for a role for the acid sphingomyelinase (ASM)–ceramide system in the therapeutic action of antidepressants. Sphingomyelin is a complex lipid in the brain and a major component of cell membranes. It is catabolized into ceramide and phosphorylcholine by ASM, a lysosomal enzyme. Ceramide is the precursor of all complex sphingolipids and has a major role as a lipid second messenger in cell signaling pathways that can influence cell survival, proliferation, differentiation, and other processes. Gulbins and colleagues previously proposed a hypothesis for the actions of antidepressants in which these drugs gradually accumulate in acidic intracellular vesicles in the brain, such as lysosomes. The authors also previously found increased activity of ASM in patients with major depression. In the current study, they directly test whether the effects of antidepressants involve inhibiting the ASM-ceramide system.

This new study demonstrates that the treatment of wild-type (WT) mice with the antidepressants amitriptyline or fluoxetine reduces ASM activity and expression and ceramide levels in a dose-dependent manner in the hippocampus. Hippocampal atrophy and reduced neurogenesis are associated with depression, and ASM-deficient transgenic mice had increased hippocampal neurogenesis and reduced depression-like behavior. In addition, antidepressant treatment increased hippocampal neurogenesis and reduced depression-like behavior in WT mice but did not have these effects in ASM-deficient mice. Fendiline, an ASM inhibitor, ameliorated depression-like behaviors and increased neurogenesis in a manner similar to that of antidepressants. The authors also found that chronic stress increased ceramide levels twofold in the hippocampus. Artificially increasing ceramide levels in mice resulted in substantial decreases in neurogenesis and increases in depression-like behavior.

These findings reveal insights into the role of the ASM-ceramide system in depression and suggest that antidepressants inhibit ASM activity and ceramide production in the brain. This system may thus emerge as a target for the development of new treatments for major depression and mood disorders. The mechanisms through which ceramide can modulate neurogenesis and depression-like behaviors are important areas for future research.

E. Gulbins et al., Acid sphingomyelinase–ceramide system mediates effects of antidepressant drugs. Nat. Med. 19, 934–938 (2013). [Abstract]

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