TY  - JOUR
A1  - Gulbins, Anne
A1  - Schumacher, Fabian
A1  - Becker, Katrin Anne
A1  - Wilker, Barbara
A1  - Soddemann, Matthias
A1  - Boldrin, Francesco
A1  - Müller, Christian P.
A1  - Edwards, Michael J.
A1  - Goodman, Michael
A1  - Caldwell, Charles C.
A1  - Kleuser, Burkhard
A1  - Kornhuber, Johannes
A1  - Szabo, Ildiko
A1  - Gulbins, Erich
T1  - Antidepressants act by inducing autophagy controlled by sphingomyelin-ceramide
JF  - Molecular psychiatry
N2  - Major depressive disorder (MDD) is a common and severe disease characterized by mood changes, somatic alterations, and often suicide. MDD is treated with antidepressants, but the molecular mechanism of their action is unknown. We found that widely used antidepressants such as amitriptyline and fluoxetine induce autophagy in hippocampal neurons via the slow accumulation of sphingomyelin in lysosomes and Golgi membranes and of ceramide in the endoplasmic reticulum (ER). ER ceramide stimulates phosphatase 2A and thereby the autophagy proteins Ulk, Beclin, Vps34/Phosphatidylinositol 3-kinase, p62, and Lc3B. Although treatment with amitriptyline or fluoxetine requires at least 12 days to achieve sphingomyelin accumulation and the subsequent biochemical and cellular changes, direct inhibition of sphingomyelin synthases with tricyclodecan-9-yl-xanthogenate (D609) results in rapid (within 3 days) accumulation of ceramide in the ER, activation of autophagy, and reversal of biochemical and behavioral signs of stress-induced MDD. Inhibition of Beclin blocks the antidepressive effects of amitriptyline and D609 and induces cellular and behavioral changes typical of MDD. These findings identify sphingolipid-controlled autophagy as an important target for antidepressive treatment methods and provide a rationale for the development of novel antidepressants that act within a few days.
Y1  - 2018
U6  - https://doi.org/10.1038/s41380-018-0090-9
SN  - 1359-4184
SN  - 1476-5578
VL  - 23
IS  - 12
SP  - 2324
EP  - 2346
PB  - Nature Publ. Group
CY  - London
ER  -