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Webhofer, Christian (2013): Antidepressant activated biochemical pathways and biomarker candidates. Dissertation, LMU München: Graduate School of Systemic Neurosciences (GSN)



Most of the commonly used antidepressants block monoamine reuptake transporters to enhance serotonergic or noradrenergic neurotransmission. Effects besides or downstream of increased monoaminergic neurotransmission are poorly understood and yet presumably important for the drugs’ mode of action. In my PhD thesis I employed proteomics and metabolomics technologies combined with in silico analyses and identified cellular pathways affected by antidepressant drug treatment. DBA/2 mice were treated with paroxetine as a representative Selective Serotonin Reuptake Inhibitor (SSRI). Hippocampal protein levels were compared between chronic paroxetine- and vehicle-treated animals using in vivo 15N metabolic labeling combined with mass spectrometry. I also studied chronic changes in the hippocampus using unbiased metabolite profiling and the time course of metabolic changes with the help of a targeted polar metabolomics profiling platform. I identified profound alterations related to hippocampal energy metabolism. Glycolytic metabolite levels acutely increased while Krebs cycle metabolite levels decreased upon chronic treatment. Changes in energy metabolism were influenced by altered glycogen metabolism rather than by altered glycolytic or Krebs cycle enzyme levels. Increased energy levels were reflected by an increased ATP/ADP ratio and by increased ratios of high-to-low energy purines and pyrimidines. Paralleling the shift towards aerobic glycolysis upon paroxetine treatment I identified decreased levels of Krebs cycle and oxidative phosphorylation enzyme levels upon the antidepressant-like 15N isotope effect in high-anxiety behavior mice. In the course of my analyses I also identified GABA, galactose-6-phosphate and leucine as biomarker candidates for the assessment of chronic paroxetine treatment effects in the periphery and myo-inositol as biomarker candidate for an early assessment of chronic treatment effects. The identified antidepressant drug treatment affected molecular pathways and novel SSRI modes of action warrant consideration in antidepressant drug development efforts.