The role of ceramide in major depressive disorder.
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.
Kornhuber
Johannes
J
Department of Psychiatry and Psychotherapy, University of Erlangen, Schwabachanlage 6, 91054 Erlangen, Germany. Johannes.Kornhuber@uk-erlangen.de
Reichel
Martin
M
Tripal
Philipp
P
Groemer
Teja W
TW
Henkel
Andreas W
AW
Mühle
Christiane
C
Gulbins
Erich
E
D000928:Antidepressive Agents / Q000493:pharmacokinetics; D001921:Brain / Q000378:metabolism; D002518:Ceramides / Q000502:physiology*; D003865:Major Depressive Disorder / Q000188:drug therapy / Q000503:physiopathology* / Q000523:psychology; D004311:Double-Blind Method; D006801:Humans; D013108:Sphingomyelin Phosphodiesterase / Q000187:drug effects / Q000378:metabolism
D000928:Antidepressive Agents; D002518:Ceramides; D013108:Sphingomyelin Phosphodiesterase