The role of ceramide in major depressive disorder

  • Johannes Kornhuber
  • Martin Reichel
  • Philipp Tripal
  • Teja W. Groemer
  • Andreas W. Henkel
  • Christiane Mühle
  • Erich Gulbins


Major depression is a severe mood disorder with a lifetime prevalence of more than 10%. The pharmacokinetic hypothesis claims that a slow accumulation of antidepressant drugs by acid trapping mainly into lysosomes is responsible for the therapeutic latency and that a lysosomal target mediates the antidepressant effects. The lysosomal lipid metabolizing enzyme acid sphingomyelinase (ASM) cleaves sphingomyelin into ceramide and phosphorylcholine. In a pilot study, the activity of this enzyme was increased in peripheral blood cells of patients with major depressive disorder (MDD), making the ASM an interesting molecular target of antidepressant drugs. Indeed, several antidepressant drugs functionally inhibit ASM. The ASM/ceramide pathway might be a missing link unifying independent findings in neurobiology and the treatment of MDD such as therapeutic latency, oxidative stress, immune activation and increased risk of cardiovascular disease.


Major depressive disorder Neuroplasticity hypothesis Pharmacokinetic hypothesis Acid sphingomyelinase Amitriptyline Fluoxetine Sphingolipids Ceramide Lysosomes 


  1. 1.
    Altamura AC, Moro AR, Percudani M (1994) Clinical pharmacokinetics of fluoxetine. Clin Pharmacokinet 26:201–214CrossRefPubMedGoogle Scholar
  2. 2.
    Angst J, Brandenberger H, Herrmann B (1967) Suicid mit Opipramol (InsidonR). Psychopharmacologia 11:174–178CrossRefPubMedGoogle Scholar
  3. 3.
    Augé N, Nègre-Salvayre A, Salvayre R, Levade T (2000) Sphingomyelin metabolites in vascular cell signaling and atherogenesis. Prog Lipid Res 39:207–229CrossRefPubMedGoogle Scholar
  4. 4.
    Balon K, Riebesehl BU, Müller BW (1999) Drug liposome partitioning as a tool for the prediction of human passive intestinal absorption. Pharm Res 16:882–888CrossRefPubMedGoogle Scholar
  5. 5.
    Baumann P, Ulrich S, Eckermann G, Gerlach M, Kuss HJ, Laux G, Müller-Oerlinghausen B, Rao ML, Riederer P, Zernig G, Hiemke C (2005) The AGNP-TDM Expert Group Consensus Guidelines: focus on therapeutic monitoring of antidepressants. Dialogues Clin Neurosci 7:231–247PubMedGoogle Scholar
  6. 6.
    Belmaker RH, Agam G (2008) Major depressive disorder. N Engl J Med 358:55–68CrossRefPubMedGoogle Scholar
  7. 7.
    Bianco F, Perrotta C, Novellino L, Francolini M, Riganti L, Menna E, Saglietti L, Schuchman EH, Furlan R, Clementi E, Matteoli M, Verderio C (2009) Acid sphingomyelinase activity triggers microparticle release from glial cells. EMBO J 28:1043–1054CrossRefPubMedGoogle Scholar
  8. 8.
    Cizza G, Ravn P, Chrousos GP, Gold PW (2001) Depression: a major, unrecognized risk factor for osteoporosis? Trends Endocrinol Metab 12:198–203CrossRefPubMedGoogle Scholar
  9. 9.
    Corda S, Laplace C, Vicaut E, Duranteau J (2001) Rapid reactive oxygen species production by mitochondria in endothelial cells exposed to tumor necrosis factor-alpha is mediated by ceramide. Am J Respir Cell Mol Biol 24:762–768PubMedGoogle Scholar
  10. 10.
    Coull MA, Lowther S, Katona CLE, Horton RW (2000) Altered brain protein kinase C in depression: a post-mortem study. Eur Neuropsychopharmacol 10:283–288CrossRefPubMedGoogle Scholar
  11. 11.
    Cuvillier O, Pirianov G, Kleuser B, Vanek PG, Coso OA, Gutkind S, Spiegel S (1996) Suppression of ceramide-mediated programmed cell death by sphingosine-1-phosphate. Nature 381:800–803CrossRefPubMedGoogle Scholar
  12. 12.
    de Duve C, de Barsy T, Poole B, Trouet A, Tulkens P, van Hoof F (1974) Lysosomotropic agents. Biochem Pharmacol 23:2495–2531CrossRefPubMedGoogle Scholar
  13. 13.
    Forlenza MJ, Miller GE (2006) Increased serum levels of 8-hydroxy-2’-deoxyguanosine in clinical depression. Psychosom Med 68:1–7CrossRefPubMedGoogle Scholar
  14. 14.
    Frank MG, Hendricks SE, Bessette D, Johnson DR, Wieseler Frank JL, Burke WJ (2001) Levels of monocyte reactive oxygen species are associated with reduced natural killer cell activity in major depressive disorder. Neuropsychobiology 44:1–6CrossRefPubMedGoogle Scholar
  15. 15.
    Fu K, Konrad RJ, Hardy RW, Brissie RM, Robinson CA (2000) An unusual multiple drug intoxication case involving citalopram. J Anal Toxicol 24:648–650PubMedGoogle Scholar
  16. 16.
    Goshen I, Kreisel T, Ben-Menachem-Zidon O, Licht T, Weidenfeld J, Ben-Hur T, Yirmiya R (2008) Brain interleukin-1 mediates chronic stress-induced depression in mice via adrenocortical activation and hippocampal neurogenesis suppression. Mol Psychiatry 13:717–728CrossRefPubMedGoogle Scholar
  17. 17.
    Goshen I, Yirmiya R (2009) Interleukin-1 (IL-1): a central regulator of stress responses. Front Neuroendocrinol 30:30–45CrossRefPubMedGoogle Scholar
  18. 18.
    Gulbins E, Li PL (2006) Physiological and pathophysiological aspects of ceramide. Am J Physiol Regul Integr Comp Physiol 290:R11–R26PubMedGoogle Scholar
  19. 19.
    Gulbins E, Szabo I, Baltzer K, Lang F (1997) Ceramide-induced inhibition of T lymphocyte voltage-gated potassium channel is mediated by tyrosine kinases. Proc Natl Acad Sci USA 94:7661–7666CrossRefPubMedGoogle Scholar
  20. 20.
    Hannun YA (1996) Functions of ceramide in coordinating cellular responses to stress. Science 274:1855–1859CrossRefPubMedGoogle Scholar
  21. 21.
    Henry ME, Schmidt ME, Hennen J, Villafuerte RA, Butman ML, Tran P, Kerner LT, Cohen B, Renshaw PF (2005) A comparison of brain and serum pharmacokinetics of R-fluoxetine and racemic fluoxetine: a 19-F MRS study. Neuropsychopharmacology 30:1576–1583CrossRefPubMedGoogle Scholar
  22. 22.
    Hibbeln JR, Palmer JW, Davis JM (1989) Are disturbances in lipid-protein interactions by phospholipase-A2 a predisposing factor in affective illness? Biol Psychiatry 25:945–961CrossRefPubMedGoogle Scholar
  23. 23.
    Hofmeister R, Wiegmann K, Korherr C, Bernardo K, Kronke M, Falk W (1997) Activation of acid sphingomyelinase by interleukin-1 (IL-1) requires the IL-1 receptor accessory protein. J Biol Chem 272:27730–27736CrossRefPubMedGoogle Scholar
  24. 24.
    Howren MB, Lamkin DM, Suls J (2009) Associations of depression with C-reactive protein, IL-1, and IL-6: a meta-analysis. Psychosom Med 71:171–186CrossRefPubMedGoogle Scholar
  25. 25.
    Huwiler A, Johansen B, Skarstad A, Pfeilschifter J (2001) Ceramide binds to the CaLB domain of cytosolic phospholipase A2 and facilitates its membrane docking and arachidonic acid release. FASEB J 15:7–9PubMedGoogle Scholar
  26. 26.
    Irie M, Asami S, Nagata S, Miyata M, Kasai H (2001) Relationships between perceived workload, stress and oxidative DNA damage. Int Arch Occup Environ Health 74:153–157CrossRefPubMedGoogle Scholar
  27. 27.
    Ishizaki J, Yokogawa K, Hirano M, Nakashima E, Sai Y, Ohkuma S, Ohshima T, Ichimura F (1996) Contribution of lysosomes to the subcellular distribution of basic drugs in the rat liver. Pharm Res 13:902–906CrossRefPubMedGoogle Scholar
  28. 28.
    Karson CN, Newton JEO, Livingston R, Jolly JB, Cooper TB, Sprigg J, Komoroski RA (1993) Human brain fluoxetine concentrations. J Neuropsychiatry Clin Neurosci 5:322–329PubMedGoogle Scholar
  29. 29.
    Kölzer M, Werth N, Sandhoff K (2004) Interactions of acid sphingomyelinase and lipid bilayers in the presence of the tricyclic antidepressant desipramine. FEBS Lett 559:96–98CrossRefPubMedGoogle Scholar
  30. 30.
    Koo JW, Duman RS (2008) IL-1beta is an essential mediator of the antineurogenic and anhedonic effects of stress. Proc Natl Acad Sci USA 105:751–756CrossRefPubMedGoogle Scholar
  31. 31.
    Kornhuber J, Henkel AW, Groemer TW, Städtler S, Welzel O, Tripal P, Rotter A, Bleich S, Trapp S (2009) Lipophilic cationic drugs increase the permeability of lysosomal membranes in a cell culture system (submitted)Google Scholar
  32. 32.
    Kornhuber J, Medlin A, Bleich S, Jendrossek V, Henkel AW, Wiltfang J, Gulbins E (2005) High activity of acid sphingomyelinase in major depression. J Neural Transm 112:1583–1590CrossRefPubMedGoogle Scholar
  33. 33.
    Kornhuber J, Retz W, Riederer P (1995) Slow accumulation of psychotropic substances in the human brain: relationship to therapeutic latency of neuroleptic and antidepressant drugs? J Neural Transm Suppl 46:311–319Google Scholar
  34. 34.
    Kornhuber J, Tripal P, Reichel M, Terfloth L, Bleich S, Wiltfang J, Gulbins E (2008) Identification of new functional inhibitors of acid sphingomyelinase using a structure–property–activity relation model. J Med Chem 51:219–237CrossRefPubMedGoogle Scholar
  35. 35.
    Koumanov KS, Momchilova AB, Quinn PJ, Wolf C (2002) Ceramides increase the activity of the secretory phospholipase A2 and alter its fatty acid specificity. Biochem J 363:45–51CrossRefPubMedGoogle Scholar
  36. 36.
    Lepple-Wienhues A, Belka C, Laun T, Jekle A, Walter B, Wieland U, Welz M, Heil L, Kun J, Busch G, Weller M, Bamberg M, Gulbins E, Lang F (1999) Stimulation of CD95 (Fas) blocks T lymphocyte calcium channels through sphingomyelinase and sphingolipids. Proc Natl Acad Sci USA 96:13795–13800CrossRefPubMedGoogle Scholar
  37. 37.
    Lombardo F, Obach RS, Shalaeva MY, Gao F (2004) Prediction of human volume of distribution values for neutral and basic drugs. 2. Extended data set and leave-class-out statistics. J Med Chem 47:1242–1250CrossRefPubMedGoogle Scholar
  38. 38.
    Maes M, Smith R, Christophe A, Vandoolaeghe E, Van Gastel A, Neels H, Demedts P, Wauters A, Meltzer HY (1997) Lower serum high-density lipoprotein cholesterol (HDL-C) in major depression and in depressed men with serious suicidal attempts: relationship with immune-inflammatory markers. Acta Psychiatr Scand 95:212–221CrossRefPubMedGoogle Scholar
  39. 39.
    Marathe S, Kuriakose G, Williams KJ, Tabas I (1999) Sphingomyelinase, an enzyme implicated in atherogenesis, is present in atherosclerotic lesions and binds to specific components of the subendothelial extracellular matrix. Arterioscler Thromb Vasc Biol 19:2648–2658PubMedGoogle Scholar
  40. 40.
    Müller G, Ayoub M, Storz P, Rennecke J, Fabbro D, Pfizenmaier K (1995) PKC ζ is a molecular switch in signal transduction of TNF-α, bifunctionally regulated by ceramide and arachidonic acid. EMBO J 14:1961–1969PubMedGoogle Scholar
  41. 41.
    Musselman DL, Evans DL, Nemeroff CB (1998) The relationship of depression to cardiovascular disease: epidemiology, biology, and treatment. Arch Gen Psychiatry 55:580–592CrossRefPubMedGoogle Scholar
  42. 42.
    Ozcan ME, Gulec M, Ozerol E, Polat R, Akyol O (2004) Antioxidant enzyme activities and oxidative stress in affective disorders. Int Clin Psychopharmacol 19:89–95CrossRefPubMedGoogle Scholar
  43. 43.
    Pandey GN, Dwivedi Y, Rizavi HS, Ren X, Conley RR (2004) Decreased catalytic activity and expression of protein kinase C isozymes in teenage suicide victims: a postmortem brain study. Arch Gen Psychiatry 61:685–693CrossRefPubMedGoogle Scholar
  44. 44.
    Parker G, Gibson NA, Brotchie H, Heruc G, Rees AM, Hadzi-Pavlovic D (2006) Omega-3 fatty acids and mood disorders. Am J Psychiatry 163:969–978CrossRefPubMedGoogle Scholar
  45. 45.
    Pascual M, Valles SL, Renau-Piqueras J, Guerri C (2003) Ceramide pathways modulate ethanol-induced cell death in astrocytes. J Neurochem 87:1535–1545PubMedCrossRefGoogle Scholar
  46. 46.
    Phillips DC, Allen K, Griffiths HR (2002) Synthetic ceramides induce growth arrest or apoptosis by altering cellular redox status. Arch Biochem Biophys 407:15–24CrossRefPubMedGoogle Scholar
  47. 47.
    Qiu H, Edmunds T, Baker-Malcolm J, Karey KP, Estes S, Schwarz C, Hughes H, Van Patten SM (2003) Activation of human acid sphingomyelinase through modification or deletion of C-terminal cysteine. J Biol Chem 278:32744–32752CrossRefPubMedGoogle Scholar
  48. 48.
    Ramu Y, Xu Y, Lu Z (2006) Enzymatic activation of voltage-gated potassium channels. Nature 442:696–699CrossRefPubMedGoogle Scholar
  49. 49.
    Reichel M, Greiner E, Richter-Schmdinger T, Yedibela Ö, Tripal P, Jacobi A, Bleich S, Gulbins E, Kornhuber J (2009) Increased acid sphingomyelinase activity in peripheral blood cells of acutely intoxicated patients with alcohol dependence. Alcohol Clin Exp Res (in press)Google Scholar
  50. 50.
    Riddle EL, Rau KS, Topham MK, Hanson GR, Fleckenstein AE (2003) Ceramide-induced alterations in dopamine transporter function. Eur J Pharmacol 458:31–36CrossRefPubMedGoogle Scholar
  51. 51.
    Schütze S, Potthoff K, Machleidt T, Berkovic D, Wiegmann K, Krönke M (1992) TNF activates NF-kappa B by phosphatidylcholine-specific phospholipase C-induced “acidic” sphingomyelin breakdown. Cell 71:765–776CrossRefPubMedGoogle Scholar
  52. 52.
    Schwarz A, Futerman AH (1997) Distinct roles for ceramide and glucosylceramide at different stages of neuronal growth. J Neurosci 17:2929–2938PubMedGoogle Scholar
  53. 53.
    Sietsma H, Veldman RJ, Kok JW (2001) The involvement of sphingolipids in multidrug resistance. J Membr Biol 181:153–162PubMedGoogle Scholar
  54. 54.
    Smith EL, Schuchman EH (2008) The unexpected role of acid sphingomyelinase in cell death and the pathophysiology of common diseases. FASEB J 22:3419–3431CrossRefPubMedGoogle Scholar
  55. 55.
    Spiegel S, Cuvillier O, Edsall LC, Kohama T, Menzeleev R, Olah Z, Olivera A, Pirianov G, Thomas DM, Tu Z, Van B Jr, Wang F (1998) Sphingosine-1-phosphate in cell growth and cell death. Ann N Y Acad Sci 845:11–18CrossRefPubMedGoogle Scholar
  56. 56.
    Trapp S, Rosania GR, Horobin RW, Kornhuber J (2008) Quantitative modeling of selective lysosomal targeting for drug design. Eur Biophys J 37:1317–1328CrossRefPubMedGoogle Scholar
  57. 57.
    Videbech P, Ravnkilde B (2004) Hippocampal volume and depression: a meta-analysis of MRI studies. Am J Psychiatry 161:1957–1966CrossRefPubMedGoogle Scholar
  58. 58.
    Won JS, Singh I (2006) Sphingolipid signaling and redox regulation. Free Radic Biol Med 40:1875–1888CrossRefPubMedGoogle Scholar
  59. 59.
    Zeidan YH, Hannun YA (2007) Activation of acid sphingomyelinase by protein kinase Cδ-mediated phosphorylation. J Biol Chem 282:11549–11561CrossRefPubMedGoogle Scholar
  60. 60.
    Zha X, Pierini LM, Leopold PL, Skiba PJ, Tabas I, Maxfield FR (1998) Sphingomyelinase treatment induces ATP-independent endocytosis. J Cell Biol 140:39–47CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag 2009

Authors and Affiliations

  • Johannes Kornhuber
    • 1
  • Martin Reichel
    • 1
  • Philipp Tripal
    • 1
  • Teja W. Groemer
    • 1
  • Andreas W. Henkel
    • 1
  • Christiane Mühle
    • 1
  • Erich Gulbins
    • 2
  1. 1.Department of Psychiatry and PsychotherapyUniversity of ErlangenErlangenGermany
  2. 2.Department of Molecular BiologyUniversity of Duisburg-EssenEssenGermany

Personalised recommendations