The acid sphingomyelinase/ceramide hypothesis of major depression

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Major depression is a severe and often life-threatening mood disorder. The molecular mechanisms resulting in major depression are, however, unknown. Previously, we found increased activity of the acid sphingomyelinase (ASM) in patients suffering from major depression, consistent with the finding of the functional inhibition of the ASM by antidepressant drugs. Data generated during the first funding period demonstrate that amitriptyline and fluoxetine inhibit the ASM in the hippocampus of stressed and resting mice, resulting in reduction of hippocampal ceramide, increased neurogenesis and behavioural effects, events that were all absent in ASM-deficient mice receiving these antidepressant drugs. 1) Amitriptyline and fluoxetine functionally inhibit ASM in concentrations used for antidepressant therapy. In mouse models, we will now determine whether or not the neurobiological and behavioural effects of antidepressive drugs and electroconvulsive stimulation are mediated by inhibition of the ASM; 2) in cell culture models, determine whether or not ASM is involved in processes relevant for synaptic transmission; 3) in human patients, study the role of ASM as a diagnostic marker.