Acid sphingomyelinase–ceramide system mediates effects of antidepressant drugs
Open accessAbstract
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.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Prior studies suggest that several antidepressants may inhibit acid sphingomyelinase activity.
“First, prior studies suggest that several antidepressants may inhibit acid sphingomyelinase activity [10], which may prevent the infection of epithelial cells with SARS-CoV-2 [11].”
From Association between antidepressant use and reduced risk of intubation or death in hospitalized patients with COVID-19: results from an observational study (2021) · cites this paper as [10]
Functional inhibitors of acid sphingomyelinase activity, including several SSRI and non-SSRI antidepressants, may prevent infection of epithelial cells with SARS-CoV-2.
“Furthermore, a recent study [10] suggests that functional inhibitors of acid sphingomyelinase activity (FIASMA), including several SSRI and non-SSRI antidepressants, may prevent the infection of epithelial cells with SARS-CoV-2 [11].”
From Association between antidepressant use and reduced risk of intubation or death in hospitalized patients with COVID-19: results from an observational study (2021) · cites this paper as [10]
Cites
The Mouse Brain in Stereotaxic Coordinates
Paxinos, G. (2001) · Cited by 12,859 · see citing works
A Meta-Analysis of Cytokines in Major Depression
Dowlati, Y., Herrmann, N., Swardfager, W., Liu, H., Sham, L., Reim, E. K., & Lanctôt, K. L. (2010) · Biological Psychiatry · doi:10.1016/j.biopsych.2009.09.033 · Cited by 4,729 · see citing works
Requirement of hippocampal neurogenesis for the behavioral effects of antidepressants
Santarelli, L., Saxe, M., Gross, C., Surget, A., Battaglia, F., Dulawa, S., Weisstaub, N., Lee, J., Duman, R., Arancio, O., et al. (2003) · Science · doi:10.1126/science.1083328 · Cited by 4,321 · see citing works
The molecular neurobiology of depression
Krishnan, V., & Nestler, E. J. (2008) · Nature · doi:10.1038/nature07455 · Cited by 2,889 · see citing works
Associations of depression with C-reactive protein, IL-1, and IL-6: a meta-analysis.
Howren, M. B., Lamkin, D. M., & Suls, J. (2009) · Psychosomatic Medicine · doi:10.1097/psy.0b013e3181907c1b · Cited by 2,766 · see citing works
Belmaker, R. H., & Agam, G. (2008) · New England Journal of Medicine · doi:10.1056/nejmra073096 · Cited by 2,166 · see citing works
David, D. J., Samuels, B. A., Rainer, Q., Wang, J.-W., Marsteller, D., Mendez, I., Drew, M., Craig, D. A., Guiard, B. P., Guilloux, J.-P., et al. (2009) · Neuron · doi:10.1016/j.neuron.2009.04.017 · Cited by 1,267 · see citing works
Efficient in vivo manipulation of mouse genomic sequences at the zygote stage.
Lakso, M., Pichel, J. G., Gorman, J. R., Sauer, B., Okamoto, Y., Lee, E., Alt, F. W., & Westphal, H. (1996) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.93.12.5860 · Cited by 1,125 · see citing works
IL-1β is an essential mediator of the antineurogenic and anhedonic effects of stress
Koo, J. W., & Duman, R. S. (2008) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0708092105 · Cited by 862 · see citing works
Hippocampal neurogenesis: opposing effects of stress and antidepressant treatment
Warner‐Schmidt, J. L., & Duman, R. S. (2006) · Hippocampus · doi:10.1002/hipo.20156 · Cited by 787 · see citing works
Functional dichotomy of neutral and acidic sphingomyelinases in tumor necrosis factor signaling
Wiegmann, K., Schütze, S., Machleidt, T., Witte, D., & Krönke, M. (1994) · Cell · doi:10.1016/0092-8674(94)90275-5 · Cited by 714 · see citing works
CD95 Signaling via Ceramide-rich Membrane Rafts
Grassmé, H., Jekle, A., Riehle, A., Schwarz, H., Berger, J., Sandhoff, K., Kolesnick, R., & Gulbins, E. (2001) · Journal of Biological Chemistry · doi:10.1074/jbc.m101207200 · Cited by 637 · see citing works
Self-citationKim, M. Y., Linardic, C. M., Obeid, L. M., & Hannun, Y. A. (1991) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(18)52461-3 · Cited by 628 · see citing works
Epidemiology of comorbid coronary artery disease and depression
Rudisch, B. E., & Nemeroff, C. B. (2003) · Biological Psychiatry · doi:10.1016/s0006-3223(03)00587-0 · Cited by 551 · see citing works
Host defense against Pseudomonas aeruginosa requires ceramide-rich membrane rafts
Grassmé, H., Jendrossek, V., Riehle, A., von Kürthy, G., Berger, J., Schwarz, H., Weller, M., Kolesnick, R., & Gulbins, E. (2003) · Nature Medicine · doi:10.1038/nm823 · Cited by 536 · see citing works
Self-citationAcid sphingomyelinase deficient mice: a model of types A and B Niemann–Pick disease
Horinouchi, K., Erlich, S. S., Perl, D. P., Ferlinz, K., Bisgaier, C. L., Sandhoff, K., Desnick, R. J., Stewart, C. L., & Schuchman, E. H. (1995) · Nature Genetics · doi:10.1038/ng0795-288 · Cited by 471 · see citing works
PI3K/Akt and CREB regulate adult neural hippocampal progenitor proliferation and differentiation
Peltier, J., O'Neill, A., & Schaffer, D. V. (2007) · Developmental Neurobiology · doi:10.1002/dneu.20506 · Cited by 443 · see citing works
Mathias, S., Younes, A., Kan, C.-C., Orlow, I., Joseph, C. K., & Kolesnick, R. (1993) · Science · doi:10.1126/science.8424175 · Cited by 433 · see citing works
Raft ceramide in molecular medicine
Gulbins, E., & Kolesnick, R. (2003) · Oncogene · doi:10.1038/sj.onc.1207146 · Cited by 425 · see citing works
Self-citationBrenner, B., Koppenhoefer, U., Weinstock, C., Linderkamp, O., Lang, F. J. W., & Gulbins, E. (1997) · Journal of Biological Chemistry · doi:10.1074/jbc.272.35.22173 · Cited by 297 · see citing works
Self-citationKornhuber, J., Tripal, P., Reichel, M., Terfloth, L., Bleich, S., Wiltfang, J., & Gulbins, E. (2007) · Journal of Medicinal Chemistry · doi:10.1021/jm070524a · Cited by 225 · see citing works
Self-citationDepression, inflammation, and pain in patients with rheumatoid arthritis.
Kojima, M., Kojima, T., Suzuki, S., Oguchi, T., Oba, M., Tsuchiya, H., Sugiura, F., Kanayama, Y., Furukawa, T. A., Tokudome, S., et al. (2009) · Arthritis Care & Research · doi:10.1002/art.24647 · Cited by 217 · see citing works
Kölzer, M., Werth, N., & Sandhoff, K. (2004) · FEBS Letters · doi:10.1016/s0014-5793(04)00033-x · Cited by 200 · see citing works
Ranganathan, R., Sawin, E. R., Trent, C., et al. (2001) · Journal of Neuroscience · doi:10.1523/jneurosci.21-16-05871.2001 · Cited by 188 · see citing works
Lepple‐Wienhues, A., Belka, C., Laun, T., Jekle, A., Walter, B., Wieland, U., Welz, M., Heil, L., Kun, J., Busch, G. L., et al. (1999) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.96.24.13795 · Cited by 180 · see citing works
Self-citationDempsey, C. M., Mackenzie, S. M., Gargus, A., Blanco, G., & Sze, J. Y. (2005) · Genetics · doi:10.1534/genetics.104.032540 · Cited by 157 · see citing works
High activity of acid sphingomyelinase in major depression
Kornhuber, J., Medlin, A., Bleich, S., Jendrossek, V., Henkel, A. W., Wiltfang, J., & Gulbins, E. (2005) · Journal of Neural Transmission · doi:10.1007/s00702-005-0374-5 · Cited by 143 · see citing works
Self-citationCOX-2 inhibitors as antidepressants and antipsychotics: clinical evidence.
Müller, N. (2010) · PubMed · Cited by 122 · see citing works
Zhang, Y., Li, X., Carpinteiro, A., & Gulbins, E. (2008) · The Journal of Immunology · doi:10.4049/jimmunol.181.6.4247 · Cited by 109 · see citing works
Self-citationBrink, C. B., Harvey, B. H., & Brand, L. (2006) · Recent Patents on CNS Drug Discovery · doi:10.2174/157488906775245327 · Cited by 67 · see citing works
Syntaxin 4 Is Required for Acid Sphingomyelinase Activity and Apoptotic Function
Perrotta, C., Bizzozero, L., Cazzato, D., Morlacchi, S., Assi, E., Simbari, F., Zhang, Y., Gulbins, E., Bassi, M. T., Rosa, P., et al. (2010) · Journal of Biological Chemistry · doi:10.1074/jbc.m110.139287 · Cited by 66 · see citing works
Self-citationThe AGNP-TDM Expert Group Consensus Guidelines: focus on therapeutic monitoring of antidepressants
Baumann, P., Ulrich, S., Eckermann, G., Gerlach, M., Kuss, H., Laux, G., Müller-Oerlinghausen, B., Rao, M. L., Riederer, P. F., Zernig, G., et al. (2005) · Dialogues in Clinical Neuroscience · doi:10.31887/dcns.2005.7.3/pbaumann · Cited by 64 · see citing works
Walker, J., Graff, L., Dutz, J., & Bernstein, C. (2011) · Journal of Rheumatology Supplement · doi:10.3899/jrheum.110900 · Cited by 53 · see citing works
Stefanis, D. D., Reffo, P., Bonelli, G., et al. (2002) · Biological Chemistry · doi:10.1515/bc.2002.106 · Cited by 32 · see citing works
Niemann–Pick Disease versus acid sphingomyelinase deficiency
Lozano, J., Morales, A., Cremesti, A. E., et al. (2001) · Cell Death and Differentiation · doi:10.1038/sj.cdd.4400775 · Cited by 27 · see citing works
Sphingolipids and Atherosclerosis
Tabas, I. A. (2004) · Circulation · doi:10.1161/01.cir.0000150861.98087.56 · Cited by 22 · see citing works
Amato, D., Müller, C. P., & Badiani, A. (2012) · Psychopharmacology · doi:10.1007/s00213-012-2735-8 · Cited by 12 · see citing works
Self-citationHisaki, H., Shimasaki, H., Ueta, N., et al. (2004) · Brain Research · doi:10.1016/j.brainres.2004.05.042 · Cited by 12 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Repairing mitochondrial dysfunction in disease
Sorrentino, V., Menzies, K. J., & Auwerx, J. (2018) · Annual Review of Pharmacology and Toxicology · doi:10.1146/annurev-pharmtox-010716-104908 · Cited by 337 · see citing works
Brain membrane lipids in major depression and anxiety disorders
Müller, C. P., Reichel, M., Mühle, C., Rhein, C., Gulbins, E., & Kornhuber, J. (2015) · Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids · doi:10.1016/j.bbalip.2014.12.014 · Cited by 308 · see citing works
Self-citationHoertel, N., Sánchez-Rico, M., Vernet, R., Beeker, N., Jannot, A.-S., Neuraz, A., Salamanca, E., Paris, N., Daniel, C., Gramfort, A., et al. (2021) · Molecular Psychiatry · doi:10.1038/s41380-021-01021-4 · Cited by 269 · see citing works
Carpinteiro, A., Edwards, M. J., Hoffmann, M., Kochs, G., Gripp, B., Weigang, S., Adams, C., Carpinteiro, E., Gulbins, A., Keitsch, S., et al. (2020) · Cell Reports Medicine · doi:10.1016/j.xcrm.2020.100142 · Cited by 184 · see citing works
Self-citationThe role of serotonin in adult hippocampal neurogenesis
Alenina, N., & Klempin, F. (2015) · Behavioural Brain Research · doi:10.1016/j.bbr.2014.07.038 · Cited by 195 · see citing works
Lipids in Psychiatric Disorders and Preventive Medicine
Schneider, M., Levant, B., Reichel, M., Gulbins, E., Kornhuber, J., & Müller, C. P. (2017) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2016.06.002 · Cited by 175 · see citing works
Self-citationLDL cholesterol relates to depression, its severity, and the prospective course
Wagner, C. J., Musenbichler, C., Böhm, L., Färber, K., Fischer, A.-I., von Nippold, F., Winkelmann, M., Richter-Schmidinger, T., Mühle, C., Kornhuber, J., et al. (2019) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/j.pnpbp.2019.01.010 · Cited by 106 · see citing works
Self-citationLipidomics in Major Depressive Disorder
Walther, A., Cannistraci, C. V., Simons, K., Durán, C., Gerl, M. J., Wehrli, S., & Kirschbaum, C. (2018) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2018.00459 · Cited by 77 · see citing works
Park, M. H., Jin, H. K., & Bae, J.-S. (2020) · Experimental & Molecular Medicine · doi:10.1038/s12276-020-0399-8 · Cited by 59 · see citing works
Antidepressants and the adolescent brain
Cousins, L., & Goodyer, I. M. (2015) · Journal of Psychopharmacology · doi:10.1177/0269881115573542 · Cited by 61 · see citing works
Wu, P.-F., Han, Q.-Q., Chen, F.-F., Shen, T.-T., Li, Y.-H., Cao, Y., Chen, J.-G., & Wang, F. (2021) · Neurobiology of Stress · doi:10.1016/j.ynstr.2021.100390 · Cited by 32 · see citing works
- 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
- ORCID
- 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
- green
- www.zora.uzh.ch
- Licence
- other-oa
- www.springer.com/tdm (tdm)
- 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
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review