Abstract
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.
Similar content being viewed by others
References
Altamura AC, Moro AR, Percudani M (1994) Clinical pharmacokinetics of fluoxetine. Clin Pharmacokinet 26:201–214
Angst J, Brandenberger H, Herrmann B (1967) Suicid mit Opipramol (InsidonR). Psychopharmacologia 11:174–178
Augé N, Nègre-Salvayre A, Salvayre R, Levade T (2000) Sphingomyelin metabolites in vascular cell signaling and atherogenesis. Prog Lipid Res 39:207–229
Balon K, Riebesehl BU, Müller BW (1999) Drug liposome partitioning as a tool for the prediction of human passive intestinal absorption. Pharm Res 16:882–888
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 7:231–247
Belmaker RH, Agam G (2008) Major depressive disorder. N Engl J Med 358:55–68
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 28:1043–1054
Cizza G, Ravn P, Chrousos GP, Gold PW (2001) Depression: a major, unrecognized risk factor for osteoporosis? Trends Endocrinol Metab 12:198–203
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 24:762–768
Coull MA, Lowther S, Katona CLE, Horton RW (2000) Altered brain protein kinase C in depression: a post-mortem study. Eur Neuropsychopharmacol 10:283–288
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 381:800–803
de Duve C, de Barsy T, Poole B, Trouet A, Tulkens P, van Hoof F (1974) Lysosomotropic agents. Biochem Pharmacol 23:2495–2531
Forlenza MJ, Miller GE (2006) Increased serum levels of 8-hydroxy-2’-deoxyguanosine in clinical depression. Psychosom Med 68:1–7
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 44:1–6
Fu K, Konrad RJ, Hardy RW, Brissie RM, Robinson CA (2000) An unusual multiple drug intoxication case involving citalopram. J Anal Toxicol 24:648–650
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 13:717–728
Goshen I, Yirmiya R (2009) Interleukin-1 (IL-1): a central regulator of stress responses. Front Neuroendocrinol 30:30–45
Gulbins E, Li PL (2006) Physiological and pathophysiological aspects of ceramide. Am J Physiol Regul Integr Comp Physiol 290:R11–R26
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 94:7661–7666
Hannun YA (1996) Functions of ceramide in coordinating cellular responses to stress. Science 274:1855–1859
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 30:1576–1583
Hibbeln JR, Palmer JW, Davis JM (1989) Are disturbances in lipid-protein interactions by phospholipase-A2 a predisposing factor in affective illness? Biol Psychiatry 25:945–961
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 272:27730–27736
Howren MB, Lamkin DM, Suls J (2009) Associations of depression with C-reactive protein, IL-1, and IL-6: a meta-analysis. Psychosom Med 71:171–186
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 15:7–9
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 74:153–157
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 13:902–906
Karson CN, Newton JEO, Livingston R, Jolly JB, Cooper TB, Sprigg J, Komoroski RA (1993) Human brain fluoxetine concentrations. J Neuropsychiatry Clin Neurosci 5:322–329
Kölzer M, Werth N, Sandhoff K (2004) Interactions of acid sphingomyelinase and lipid bilayers in the presence of the tricyclic antidepressant desipramine. FEBS Lett 559:96–98
Koo JW, Duman RS (2008) IL-1beta is an essential mediator of the antineurogenic and anhedonic effects of stress. Proc Natl Acad Sci USA 105:751–756
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)
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 112:1583–1590
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 46:311–319
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 51:219–237
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 363:45–51
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 96:13795–13800
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 47:1242–1250
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 95:212–221
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 19:2648–2658
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 14:1961–1969
Musselman DL, Evans DL, Nemeroff CB (1998) The relationship of depression to cardiovascular disease: epidemiology, biology, and treatment. Arch Gen Psychiatry 55:580–592
Ozcan ME, Gulec M, Ozerol E, Polat R, Akyol O (2004) Antioxidant enzyme activities and oxidative stress in affective disorders. Int Clin Psychopharmacol 19:89–95
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 61:685–693
Parker G, Gibson NA, Brotchie H, Heruc G, Rees AM, Hadzi-Pavlovic D (2006) Omega-3 fatty acids and mood disorders. Am J Psychiatry 163:969–978
Pascual M, Valles SL, Renau-Piqueras J, Guerri C (2003) Ceramide pathways modulate ethanol-induced cell death in astrocytes. J Neurochem 87:1535–1545
Phillips DC, Allen K, Griffiths HR (2002) Synthetic ceramides induce growth arrest or apoptosis by altering cellular redox status. Arch Biochem Biophys 407:15–24
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 278:32744–32752
Ramu Y, Xu Y, Lu Z (2006) Enzymatic activation of voltage-gated potassium channels. Nature 442:696–699
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)
Riddle EL, Rau KS, Topham MK, Hanson GR, Fleckenstein AE (2003) Ceramide-induced alterations in dopamine transporter function. Eur J Pharmacol 458:31–36
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 71:765–776
Schwarz A, Futerman AH (1997) Distinct roles for ceramide and glucosylceramide at different stages of neuronal growth. J Neurosci 17:2929–2938
Sietsma H, Veldman RJ, Kok JW (2001) The involvement of sphingolipids in multidrug resistance. J Membr Biol 181:153–162
Smith EL, Schuchman EH (2008) The unexpected role of acid sphingomyelinase in cell death and the pathophysiology of common diseases. FASEB J 22:3419–3431
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 845:11–18
Trapp S, Rosania GR, Horobin RW, Kornhuber J (2008) Quantitative modeling of selective lysosomal targeting for drug design. Eur Biophys J 37:1317–1328
Videbech P, Ravnkilde B (2004) Hippocampal volume and depression: a meta-analysis of MRI studies. Am J Psychiatry 161:1957–1966
Won JS, Singh I (2006) Sphingolipid signaling and redox regulation. Free Radic Biol Med 40:1875–1888
Zeidan YH, Hannun YA (2007) Activation of acid sphingomyelinase by protein kinase Cδ-mediated phosphorylation. J Biol Chem 282:11549–11561
Zha X, Pierini LM, Leopold PL, Skiba PJ, Tabas I, Maxfield FR (1998) Sphingomyelinase treatment induces ATP-independent endocytosis. J Cell Biol 140:39–47
Acknowledgments
The work was supported by grants from DFG (GU 335/10-3, KO 947/10-1).
Conflict of interest statement
JK has received honoraria or research support from pharmaceutical companies (Merz Pharmaceuticals, GlaxoSmithKline, Bayer HealthCare, Novartis) during the last two years. The other authors do not declare any conflict of interest.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Kornhuber, J., Reichel, M., Tripal, P. et al. The role of ceramide in major depressive disorder. Eur Arch Psychiatry Clin Neurosci 259 (Suppl 2), 199–204 (2009). https://doi.org/10.1007/s00406-009-0061-x
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00406-009-0061-x