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.
Highlights
Selective Serotonin Reuptake Inhibitors (SSRIs) have been used as preferred antidepressant medications for several decades, over one third of major depressive disorder (MDD) patients do not respond to SSRI treatment[1]
We found that purine/pyrimidine metabolism proteins including S-adenosyl-L-homocysteine hydrolase (AdoHcyase), S-adenosyl-L-homocysteine hydrolase 2 (AdoHcyase 2), guanine deaminase (GDA), inosine triphosphate pyrophosphatase (ITPase), purine nucleoside phosphorylase (PNP) and UMP-CMP kinase (UMP/CMPK) were differentially expressed between the paroxetine-treated mice into long-time floating (PLF) and PSF groups (Fig. 2c)
We submit that paroxetine-treated mice exhibiting no forced swim test (FST) floating time difference with vehicle-treated mice are non-responsive towards SSRI treatment
Summary
Selective Serotonin Reuptake Inhibitors (SSRIs) have been used as preferred antidepressant medications for several decades, over one third of major depressive disorder (MDD) patients do not respond to SSRI treatment[1]. Few genetic polymorphisms identified have achieved genome-wide significance or were consistently replicated across studies, suggesting that alternative strategies need to be explored to realize molecular stratification of antidepressant treatment response[2,3]. Recent findings obtained with clinical specimens indicate a potent role of metabolites for separating antidepressant responder and non-responder patients. Several pathways involved in dihydroxyphenylacetic acid, serotonin, and gamma tocopherol synthesis have been implicated in separating sertraline responder and non-responder patients[5]. Despite these promising findings with peripheral patient specimens an understanding of the molecular changes in response to SSRI treatment occurring in the brain is still missing. A systematic investigation of affected pathways in the brain and a correlation with the periphery will eventually allow the implementation of biosignatures capable of differentiating antidepressant responders and non-responders
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