Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter
  • Published:

Acid sphingomyelinase–ceramide system mediates effects of antidepressant drugs

Abstract

Major depression is a highly prevalent severe mood disorder that is treated with antidepressants. The molecular targets of antidepressants require definition. We investigated the role of the acid sphingomyelinase (Asm)-ceramide system as a target for antidepressants. Therapeutic concentrations of the antidepressants amitriptyline and fluoxetine reduced Asm activity and ceramide concentrations in the hippocampus, increased neuronal proliferation, maturation and survival and improved behavior in mouse models of stress-induced depression. Genetic Asm deficiency abrogated these effects. Mice overexpressing Asm, heterozygous for acid ceramidase, treated with blockers of ceramide metabolism or directly injected with C16 ceramide in the hippocampus had higher ceramide concentrations and lower rates of neuronal proliferation, maturation and survival compared with controls and showed depression-like behavior even in the absence of stress. The decrease of ceramide abundance achieved by antidepressant-mediated inhibition of Asm normalized these effects. Lowering ceramide abundance may thus be a central goal for the future development of antidepressants.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Amitriptyline and fluoxetine reduce hippocampal ceramide concentrations by inhibiting Asm activity.
Figure 2: The Asm-ceramide system is required for the neurobiological effects of antidepressants.
Figure 3: Behavioral effects of antidepressant drugs can be mediated by the inhibition of acid sphingomyelinase.
Figure 4: Hippocampal ceramide has a crucial role in depression-like phenotypes.

Similar content being viewed by others

References

  1. Belmaker, R.H. & Agam, G. Major depressive disorder. N. Engl. J. Med. 358, 55–68 (2008).

    Article  CAS  Google Scholar 

  2. Howren, M.B., Lamkin, D.M. & Suls, J. Associations of depression with C-reactive protein, IL-1, and IL-6: a meta-analysis. Psychosom. Med. 71, 171–186 (2009).

    Article  CAS  Google Scholar 

  3. Dowlati, Y. et al. A meta-analysis of cytokines in major depression. Biol. Psychiatry 67, 446–457 (2010).

    Article  CAS  Google Scholar 

  4. Krishnan, V. & Nestler, E.J. The molecular neurobiology of depression. Nature 455, 894–902 (2008).

    Article  CAS  Google Scholar 

  5. Brink, C.B., Harvey, B.H. & Brand, L. Tianeptine: a novel atypical antidepressant that may provide new insights into the biomolecular basis of depression. Recent Pat. CNS Drug Discov. 1, 29–41 (2006).

    Article  CAS  Google Scholar 

  6. Santarelli, L. et al. Requirement of hippocampal neurogenesis for the behavioral effects of antidepressants. Science 301, 805–809 (2003).

    Article  CAS  Google Scholar 

  7. Koo, J.W. & Duman, R.S. IL-1β is an essential mediator of the antineurogenic and anhedonic effects of stress. Proc. Natl. Acad. Sci. USA 105, 751–756 (2008).

    Article  CAS  Google Scholar 

  8. David, D.J. et al. Neurogenesis-dependent and -independent effects of fluoxetine in an animal model of anxiety/depression. Neuron 62, 479–493 (2009).

    Article  CAS  Google Scholar 

  9. Warner-Schmidt, J.L. & Duman, R.S. Hippocampal neurogenesis: opposing effects of stress and antidepressant treatment. Hippocampus 16, 239–249 (2006).

    Article  CAS  Google Scholar 

  10. Gulbins, E. & Kolesnick, R. Raft ceramide in molecular medicine. Oncogene 22, 7070–7077 (2003).

    Article  CAS  Google Scholar 

  11. Grassmé, H. et al. CD95 signaling via ceramide-rich membrane rafts. J. Biol. Chem. 276, 20589–20596 (2001).

    Article  Google Scholar 

  12. Perrotta, C. et al. Syntaxin 4 is required for acid sphingomyelinase activity and apoptotic function. J. Biol. Chem. 285, 40240–40251 (2010).

    Article  CAS  Google Scholar 

  13. Grassmé, H. et al. Host defense against Pseudomonas aeruginosa requires ceramide-rich membrane rafts. Nat. Med. 9, 322–330 (2003).

    Article  Google Scholar 

  14. Baumann, P. et al. The AGNP-TDM Expert Group Consensus Guidelines: focus on therapeutic monitoring of antidepressants. Dialogues Clin. Neurosci. 7, 231–247 (2005).

    PubMed  PubMed Central  Google Scholar 

  15. Kölzer, M., Werth, N. & Sandhoff, K. Interactions of acid sphingomyelinase and lipid bilayers in the presence of the tricyclic antidepressant desipramine. FEBS Lett. 559, 96–98 (2004).

    Article  Google Scholar 

  16. Kornhuber, J. et al. Identification of new functional inhibitors of acid sphingomyelinase using a structure-property-activity relation model. J. Med. Chem. 51, 219–237 (2008).

    Article  CAS  Google Scholar 

  17. Ranganathan, R., Sawin, E.R., Trent, C. & Horvitz, H.R. Mutations in the Caenorhabditis elegans serotonin reuptake transporter MOD-5 reveal serotonin-dependent and -independent activities of fluoxetine. J. Neurosci. 21, 5871–5884 (2001).

    Article  CAS  Google Scholar 

  18. Dempsey, C.M., Mackenzie, S.M., Gargus, A., Blanco, G. & Sze, J.Y. Serotonin (5HT), fluoxetine, imipramine and dopamine target distinct 5HT receptor signaling to modulate Caenorhabditis elegans egg-laying behavior. Genetics 169, 1425–1436 (2005).

    Article  CAS  Google Scholar 

  19. De Stefanis, D. et al. Increase in ceramide level alters the lysosomal targeting of cathepsin D prior to onset of apoptosis in HT-29 colon cancer cells. Biol. Chem. 383, 989–999 (2002).

    Article  CAS  Google Scholar 

  20. Hisaki, H. et al. In vivo influence of ceramide accumulation induced by treatment with a glucosylceramide synthase inhibitor on ischemic neuronal cell death. Brain Res. 1018, 73–77 (2004).

    Article  CAS  Google Scholar 

  21. Peltier, J., O'Neill, A. & Schaffer, D.V. PI3K and CREB regulate adult neural hippocampal progenitor proliferation and differentiation. Dev. Neurobiol. 67, 1348–1361 (2007).

    Article  CAS  Google Scholar 

  22. Zhang, Y., Li, X., Carpinteiro, A. & Gulbins, E. Acid sphingomyelinase amplifies redox signaling in Pseudomonas aeruginosa–induced macrophage apoptosis. J. Immunol. 181, 4247–4254 (2008).

    Article  CAS  Google Scholar 

  23. Mathias, S. et al. Activation of the sphingomyelin signaling pathway in intact EL4 cells and in a cell-free system by IL-1 β. Science 259, 519–522 (1993).

    Article  CAS  Google Scholar 

  24. Wiegmann, K., Schütze, S., Machleidt, T., Witte, D. & Krönke, M. Functional dichotomy of neutral and acidic sphingomyelinases in tumor necrosis factor signaling. Cell 78, 1005–1015 (1994).

    Article  CAS  Google Scholar 

  25. Kim, M.Y., Linardic, C., Obeid, L. & Hannun, Y. Identification of sphingomyelin turnover as an effector mechanism for the action of tumor necrosis factor α and γ-interferon. Specific role in cell differentiation. J. Biol. Chem. 266, 484–489 (1991).

    CAS  PubMed  Google Scholar 

  26. Brenner, B. et al. Fas- or ceramide-induced apoptosis is mediated by a Rac1-regulated activation of Jun N-terminal kinase/p38 kinases and GADD153. J. Biol. Chem. 272, 22173–22181 (1997).

    Article  CAS  Google Scholar 

  27. Lepple-Wienhues, A. et al. Stimulation of CD95 (Fas) blocks T lymphocyte calcium channels through sphingomyelinase and sphingolipids. Proc. Natl. Acad. Sci. USA 96, 13795–13800 (1999).

    Article  CAS  Google Scholar 

  28. Müller, N. COX-2 inhibitors as antidepressants and antipsychotics: clinical evidence. Curr. Opin. Investig. Drugs 11, 31–42 (2010).

    PubMed  Google Scholar 

  29. Walker, J.R. et al. Psychiatric disorders in patients with immune-mediated inflammatory diseases: prevalence, association with disease activity, and overall patient well-being. J. Rheumatol. Suppl. 88, 31–35 (2011).

    Article  Google Scholar 

  30. Rudisch, B. & Nemeroff, C.B. Epidemiology of comorbid coronary artery disease and depression. Biol. Psychiatry 54, 227–240 (2003).

    Article  Google Scholar 

  31. Kojima, M. et al. Depression, inflammation, and pain in patients with rheumatoid arthritis. Arthritis Rheum. 61, 1018–1024 (2009).

    Article  Google Scholar 

  32. Tabas, I. Sphingolipids and atherosclerosis: a mechanistic connection? A therapeutic opportunity? Circulation 110, 3400–3401 (2004).

    Article  Google Scholar 

  33. Kornhuber, J. et al. High activity of acid sphingomyelinase in major depression. J. Neural Transm. 112, 1583–1590 (2005).

    Article  CAS  Google Scholar 

  34. Horinouchi, K. et al. Acid sphingomyelinase deficient mice: a model of types A and B Niemann-Pick disease. Nat. Genet. 10, 288–293 (1995).

    Article  CAS  Google Scholar 

  35. Lozano, J. et al. Niemann-Pick disease versus acid sphingomyelinase deficiency. Cell Death Differ. 8, 100–103 (2001).

    Article  CAS  Google Scholar 

  36. Lakso, M. et al. Efficient in vivo manipulation of mouse genomic sequences at the zygote stage. Proc. Natl. Acad. Sci. USA 93, 5860–5865 (1996).

    Article  CAS  Google Scholar 

  37. Amato, D., Müller, C.P. & Badiani, A. Increased drinking after intra-striatal injection of the dopamine D2/D3 receptor agonist quinpirole in the rat. Psychopharmacology (Berl.) 223, 457–463 (2012).

    Article  CAS  Google Scholar 

  38. Franklin, K.B.J. & Paxinos, G. The Mouse Brain in Stereotaxic Coordinates 3rd edn., Figure 48 (Academic Press, San Diego, 2007).

Download references

Acknowledgements

Asm-deficient mice and asm-1–deficient worms were provided by R. Kolesnick, Memorial Sloan Kettering Cancer Hospital, and E2A-Cre mice by R. Waldschütz, University Hospital Essen. The G4 antibody against Asm was provided by K. Sandhoff, University of Bonn. We thank S. Harde, B. Wilker, C. Sehl, S. Keitsch, M. Schäfer, S. Müller and E. Naschberger for excellent technical help and F. Lang for valuable discussion. Parts of the work were supported by funding from Deutsche Forschungsgemeinschaft grants GU 335/23-1, KO 947/11-1 and GRK 1302.

Author information

Authors and Affiliations

Authors

Contributions

E.G. and J.K. initiated the studies, designed experiments and supervised research. E.G., J.K. and M.W. wrote the manuscript. E.G. also performed most mouse studies. E.G., K.A.B. and G.T. performed the histological studies and developed the polyclonal Asm-specific antibody. M.P. and C.B. performed the C. elegans studies. A.L. and B.K. measured ceramide concentrations by mass spectrometry. M.W. designed some experiments and participated in BrdU stainings. H.G. performed the confocal microscopy studies. J.K., P.T. and S.S. performed experiments on the concentration-dependent inhibition of ASM by antidepressant drugs. M.R. and M.P. performed experiments on 5-HT uptake in cultured hippocampal neurons. M.R. and J.K. performed experiments on 5-HT uptake in mouse brain synaptosomes. C.H.T. and T.W.G. designed and performed synapse staining and confocal analyses. T.F.A., U.E.L. and E.G. performed behavioral experiments. C.P.M., D.A., M.R. and J.K. designed and performed hippocampal injection and microdialysis studies. C.A., J.v.B., M.R. and J.K. designed and performed electrophysiological studies in hippocampal slices. All authors discussed the results and commented on the manuscript.

Corresponding authors

Correspondence to Erich Gulbins or Johannes Kornhuber.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–13, Supplementary Notes 1–3 and Supplementary Methods (PDF 21987 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Gulbins, E., Palmada, M., Reichel, M. et al. Acid sphingomyelinase–ceramide system mediates effects of antidepressant drugs. Nat Med 19, 934–938 (2013). https://doi.org/10.1038/nm.3214

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nm.3214

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing