Breakthrough in depression treatment

Previously unstudied effect of common antidepressants identified as main effect

The most important cause of depression was previously thought to be reduced signal transmission at the contact points between neurons due to neurotransmitters such as serotonin and noradrenaline. The mood-lifting effect of common medication was ascribed to a blocking of the reuptake process, which increases the concentration of the neurotransmitters at the contact points. Now there is increasing evidence pointing towards neuronal plasticity, i.e. the formation of new neurons in the brain, being diminished in depressive patients. A team of researchers led by Prof. Dr. Erich Gulbins, Department of Molecular Biology at the University Hospital of the University of Duisburg-Essen, and Prof. Dr. Johannes Kornhuber, Department of Psychiatry and Psychotherapy at Universitätsklinikum Erlangen, have now decoded a cytological mechanism that supports this view but which also identifies a previously disregarded effect of commonly used antidepressants as the actual main effect. The researchers recently published their findings in Nature Medicine.*

Up to ten percent of the population suffer from the psychological disorder once or repeatedly in life. While the symptoms can often be treated successfully with antidepressants, the known treatments do not work on a significant percentage of those affected.

Since it is still insufficiently understood how these medications function, scientific solutions have been lacking until now. The reuptake inhibition at the brain’s synapses was an inadequate explanation. In collaboration with researchers from Potsdam, Tübingen, Basel and Zurich, Erich Gulbin’s and Johannes Kornhuber’s teams investigated the role certain lipids known as ceramides play in the formation of new cells in the brain – and what they found out was surprising.

Lipids are water-insoluble natural materials such as fats and oils. Ceramide is formed by the lipid sphingomyelin when an enzyme called acid sphingomyelinase (ASM) is activated. The researchers found that the higher the ceramide level, the more impaired the formation of new neurons in the brain. If depression is caused by a lack of new cells forming, increased ASM activity and the resulting cellular accumulation of ceramide play a key role in the development of the illness.

The researchers based their work on the observation that acid sphingomyelinase activity seems to be increased in depressive patients. Mice were genetically modified to produce increased ceramide levels. It was found that too much ceramide in the brain leads to depression-like behaviour in mice. At the same time, the researchers were able to prove that many of the already known antidepressants inhibit acid sphingomyelinase and are thus able to reduce the ceramide levels in the mice’s brains. These effects have no direct connection to the pharmacological regulation of neurotransmitters and have thus not been studied in detail so far.

This means that substances that inhibit ASM activity or lower the concentration of ceramide in the brain in some other way have an antidepressant effect – an insight that could solve one of the big mysteries that researchers have faced regarding common antidepressants: the latency period. It frequently takes several weeks until the mood-lifting effect sets in even though reuptake inhibition sets in immediately. The increase in cellular vitality in the brain through ASM inhibition is a process that can indeed take weeks, however. The team’s research results also mean that the inhibition of ASM – previously seen as an effect of common antidepressants that could be disregarded – is where the actual antidepressant effect of these substances comes from.

The working groups led by Johannes Kornhuber and Erich Gulbins have already been able identify a large number of further substances that lead to an inhibition of acid sphingomyelinase in the past. The researchers now hope their new insights will lead to the development of more effective, more specific and faster-acting treatments for depression while at the same time reducing side effects.

* Nature Medicine: “Acid sphingomyelinase–ceramide system mediates effects of antidepressant drugs”, Erich Gulbins1,2, Monica Palmada1, Martin Reichel3, Anja Lüth4, Christoph Böhmer1, Davide Amato3, Christian P Müller3, Carsten H Tischbirek3, Teja W Groemer3, Ghazaleh Tabatabai5,6, Katrin A Becker1, Philipp Tripal3, Sven Staedtler3, Teresa F Ackermann7, Johannes van Brederode8, Christian Alzheimer8, Michael Weller5, Undine E Lang9, Burkhard Kleuser4, Heike Grassmé1 & Johannes Kornhuber3, doi: 10.1038/nm.3214

Further information:

Prof. Dr. Erich Gulbins
Department of Molecular Biology, University Hospital, University of Duisburg-Essen
Phone: +49 (0)201 723 3118
erich.gulbins@uni-due.de

Prof. Dr. Johannes Kornhuber
Department of Physiatry and Psychotherapy, Universitätsklinikum Erlangen
Phone: +49 (0)9131 85 34166
johannes.kornhuber@uk-erlangen.de