Cited by 384Sphingolipid Metabolism and SignalingTreatment of Major DepressionTryptophan and brain disorders

Acid sphingomyelinase–ceramide system mediates effects of antidepressant drugs

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Gulbins, Erich, Palmada, Monica, Reichel, Martin, Lüth, Anja, Böhmer, Christoph, Amato, Davide, Müller, Christian P, Tischbirek, Carsten H +13 more·2013·Nature Medicine

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.

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Crossref · 10.1038/nm.3214

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Authors
Gulbins, E., Palmada, M., Reichel, M., Lüth, A., Böhmer, C., Amato, D., Müller, C. P., Tischbirek, C. H., Groemer, T. W., Tabatabai, G., Becker, K. A., Tripal, P., Staedtler, S., Ackermann, T. F., van Brederode, J., Alzheimer, C., Weller, M., Lang, U. E., Kleuser, B., Grassmé, H., & Kornhuber, J.
Affiliations
  • University of Duisburg-Essen (DE)
  • Friedrich-Alexander-Universität Erlangen-Nürnberg (DE)
  • University of Potsdam (DE)
  • University Hospital Zurich (CH)
  • University of Tübingen (DE)
  • University Hospital of Basel (CH)
Corresponding author
  • Gulbins, Erich
  • Kornhuber, Johannes
Venue
Nature Medicine
Published
2013-06-16
Volume
19
Issue
7
Pages
934-938
ISSN
  • 1078-8956 (ISSN-L)
  • 1546-170X
OpenAlex
W2004684279
Cited by
384
References
38
Citations by year
2026: 29 · 2025: 27 · 2024: 28 · 2023: 28 · 2022: 37 · 2021: 37 · 2020: 37 · 2019: 27 · 2018: 31 · 2017: 33 · 2016: 30 · 2015: 26 · 2014: 10 · 2013: 4
FWCI
10.44
Type
journal article
Language
en
Open access
Locations
  • Nature Medicine (publishedVersion)
  • PubMed (publishedVersion)
  • Zurich Open Repository and Archive (University of Zurich) (acceptedVersion, other-oa)
  • publish.UP (University of Potsdam) (submittedVersion)
  • OpenAgrar (submittedVersion)
  • Zurich Open Repository and Archive (University of Zurich) (submittedVersion, other-oa)
  • Zurich Open Repository and Archive (University of Zurich)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Sphingolipid Metabolism and Signaling
  • Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
  • Life Sciences › Neuroscience › Biological Psychiatry › Tryptophan and brain disorders
Keywords
acid sphingomyelinase, ceramide, antidepressants, major depressive disorder, amitriptyline, fluoxetine, hippocampus, neuronal proliferation, neuronal maturation, neuronal survival, stress-induced depression, acid ceramidase, C16-ceramide
MeSH terms
Animals, Antidepressive Agents, Cells, Cultured, Ceramides, Major Depressive Disorder, Embryo, Mammalian, Female, Humans, Male, Mice, Inbred C57BL, Sphingomyelin Phosphodiesterase, Signal Transduction, Caenorhabditis elegans, Animals, Genetically Modified, Mice

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