Antidepressant activated biochemical pathways and biomarker candidates

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.