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Abstract:
Selective Serotonin Reuptake Inhibitors (SSRIs) are commonly used drugs
for the treatment of psychiatric diseases including major depressive
disorder (MDD). For unknown reasons a substantial number of patients do
not show any improvement during or after SSRI treatment. We treated
DBA/2J mice for 28 days with paroxetine and assessed their behavioral
response with the forced swim test (FST). Paroxetine-treated long-time
floating (PLF) and paroxetine-treated short-time floating (PSF) groups
were stratified as proxies for drug non-responder and responder mice,
respectively. Proteomics and metabolomics profiles of PLF and PSF groups
were acquired for the hippocampus and plasma to identify molecular
pathways and biosignatures that stratify paroxetine-treated mouse
sub-groups. The critical role of purine and pyrimidine metabolisms for
chronic paroxetine treatment response in the mouse was further
corroborated by pathway protein expression differences in both mice and
patients that underwent chronic antidepressant treatment. The integrated
- omics data indicate purine and pyrimidine metabolism pathway activity
differences between PLF and PSF mice. Furthermore, the pathway protein
levels in peripheral specimens strongly correlated with the
antidepressant treatment response in patients. Our results suggest that
chronic SSRI treatment differentially affects purine and pyrimidine
metabolisms, which may explain the heterogeneous antidepressant
treatment response and represents a potential biosignature.
