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Transl Psychiatry. 2017 Apr 4;7(4):e1078. doi: 10.1038/tp.2017.39.

Delineation of molecular pathway activities of the chronic antidepressant treatment response suggests important roles for glutamatergic and ubiquitin-proteasome systems.

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Department of Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Munich, Germany.
Department of Stress Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry, Munich, Germany.
Phenoquest AG, Martinsried, Germany.
Department of Clinical Research, Max Planck Institute of Psychiatry, Munich, Germany.
Division of Signal Transduction, Beth Israel Deaconess Medical Center, Boston, MA, USA.
Department of Medicine, Harvard Medical School, Boston, MA, USA.
Division of Experimental Psychiatry, Focus Program Translational Neuroscience, Department of Psychiatry and Psychotherapy, Johannes Gutenberg University Medical Center, Mainz, Germany.


The aim of this study was to identify molecular pathways related to antidepressant response. We administered paroxetine to the DBA/2J mice for 28 days. Following the treatment, the mice were grouped into responders or non-responders depending on the time they spent immobile in the forced swim test. Hippocampal metabolomics and proteomics analyses revealed that chronic paroxetine treatment affects glutamate-related metabolite and protein levels differentially in the two groups. We found significant differences in the expression of N-methyl-d-aspartate receptor and neuronal nitric oxide synthase proteins between the two groups, without any significant alterations in the respective transcript levels. In addition, we found that chronic paroxetine treatment altered the levels of proteins associated with the ubiquitin-proteasome system (UPS). The soluble guanylate cyclase-β1, proteasome subunit α type-2 and ubiquitination levels were also affected in peripheral blood mononuclear cells from antidepressant responder and non-responder patients suffering from major depressive disorder. We submit that the glutamatergic system and UPS have a crucial role in the antidepressant treatment response in both mice and humans.

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