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. DOI: https://doi.org/10. 1038/nm.3214 Posted at the Zurich Open Repository and Archive, University of Zurich ZORA URL: https://doi.org/10.5167/uzh-79905 Accepted Version Originally published at: 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; Grassme, H; Kornhuber, J (2013). Acid sphingomyelinaseceramide system mediates effects of antidepressant drugs. Nature Medicine, 19 (7) Major depression may be triggered by psychological stress, inflammatory cytokines, and dysfunction of the hypothalamic-pituitary-adrenal axis, etc. 1-4 .The previously held monoamine hypothesis for the action of antidepressants has been questioned because the antidepressant effect of these drugs is not clearly associated with their monoaminergic effect; in fact, the antidepressant tianeptine is even a serotonin reuptake enhancer 5 . Furthermore, the direct effect on monoamines contrasts with the delay of antidepressant effects in patients. Recent concepts of the pathogenesis of major depression suggest a change of cellular plasticity predominantly in the hippocampus and a shift in the balance between neurogenic and antiapoptotic events that leads to neurodegeneration and hippocampal atrophy [6][7][8][9] . Antidepressants increase neurogenesis and reverse hippocampal atrophy associated with major depression 9 .Here, we tested the role of the acid sphingomyelinase (EC 3.1.4.12, sphingomyelin phosphodiesterase, human protein: ASM, murine protein: Asm, gene symbol: Smpd1) and ceramide system as a target for antidepressants. Asm is ubiquitously expressed and releases ceramide from sphingomyelin, predominantly in lysosomes but also in secretory lysosomes and on the plasma membrane 10-13 .The antidepres...

BackgroundThe obstructive sleep apnea syndrome (OSAS) is characterized by temporary cerebral hypoxia which can cause cognitive dysfunction. On the other hand, hypoxia induced neurocognitive deficits are detectable after general anesthesia.The objective of this study was to evaluate the impact of a high risk of OSAS on the postoperative cognitive dysfunction after intravenous anesthesia.MethodsIn this single center trial between June 2012 and June 2013 43 patients aged 55 to 80 years with an estimated hospital stay of at least 3 days undergoing surgery were enrolled. Patients were screened for a high risk of OSAS using the STOP-BANG test. The cognitive function was assessed using a neuropsychological test battery, including the DemTect test for cognitive impairment and the RMBT test for memory, the day before surgery and within 36 h after extubation.ResultsTwenty-two of the 43 analyzed patients were identified as patients with a high risk of OSAS. Preoperatively, OSAS patients showed a significant worse performance only for the DemTect (p = 0.0043). However, when comparing pre- and postoperative test results, the OSAS patients did not show a significant loss in any test but significantly improved in RMBT test, whereas the control group showed a significant worse performance in three of eight tests. In five tests, we found a significant difference between the two groups with respect to the change from pre- to postoperative cognitive function.ConclusionPatients with a high risk of OSAS showed a less impairment of memory function and work memory performance after intravenous anesthesia. This might be explained by a beneficial effect of intrinsic hypoxic preconditioning in these patients.

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