title: Purine and pyrimidine metabolism: Convergent evidence on chronic antidepressant treatment response in mice and humans.
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.
authors.affiliation: Max Planck Institute of Psychiatry, Department of Translational Research in Psychiatry, 80804, Munich, Germany.
authors.forename: Dong Ik
authors.initials: DI
authors.lastname: Park
authors.affiliation: Max Planck Institute of Psychiatry, Department of Stress Neurobiology and Neurogenetics, 80804 Munich, Germany.
authors.forename: Carine
authors.initials: C
authors.lastname: Dournes
authors.affiliation: Phenoquest AG, 82152 Martinsried, Germany.
authors.forename: Inge
authors.initials: I
authors.lastname: Sillaber
authors.affiliation: Max Planck Institute of Psychiatry, Department of Clinical Research, 80804 Munich, Germany.
authors.forename: Manfred
authors.initials: M
authors.lastname: Uhr
authors.affiliation: Division of Signal Transduction, Beth Israel Deaconess Medical Center, and Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: John M
authors.initials: JM
authors.lastname: Asara
authors.affiliation: Max Planck Institute of Psychiatry, Department of Stress Neurobiology and Neurogenetics, 80804 Munich, Germany.
authors.forename: Nils C
authors.initials: NC
authors.lastname: Gassen
authors.affiliation: Max Planck Institute of Psychiatry, Department of Stress Neurobiology and Neurogenetics, 80804 Munich, Germany.
authors.forename: Theo
authors.initials: T
authors.lastname: Rein
authors.affiliation: Max Planck Institute of Psychiatry, Department of Clinical Research, 80804 Munich, Germany.
authors.forename: Marcus
authors.initials: M
authors.lastname: Ising
authors.affiliation: Max Planck Institute of Psychiatry, Department of Translational Research in Psychiatry, 80804, Munich, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Webhofer
authors.affiliation: Max Planck Institute of Psychiatry, Department of Stress Neurobiology and Neurogenetics, 80804 Munich, Germany.
authors.forename: Michaela D
authors.initials: MD
authors.lastname: Filiou
authors.affiliation: Max Planck Institute of Psychiatry, Department of Translational Research in Psychiatry, 80804, Munich, Germany.|Experimental Psychiatry, Department of Psychiatry and Psychotherapy &Focus Program Translational Neuroscience, Johannes Gutenberg University Medical Center, 55128 Mainz, Germany.
authors.forename: Marianne B
authors.initials: MB
authors.lastname: Müller
authors.affiliation: Max Planck Institute of Psychiatry, Department of Translational Research in Psychiatry, 80804, Munich, Germany.
authors.forename: Christoph W
authors.initials: CW
authors.lastname: Turck
mesh_terms: D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology*; D001522:Behavior, Animal / Q000187:drug effects; D003865:Major Depressive Disorder / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D006801:Humans; D008297:Male; D055442:Metabolome; D051379:Mice; D008811:Mice, Inbred DBA; D017374:Paroxetine / Q000494:pharmacology*; D020543:Proteome / Q000378:metabolism; D011687:Purines / Q000378:metabolism*; D011743:Pyrimidines / Q000378:metabolism*; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology*; D013550:Swimming; D013997:Time Factors
chemical_list: D000928:Antidepressive Agents; D017374:Paroxetine; D020543:Proteome; D011687:Purines; D011743:Pyrimidines; D017367:Selective Serotonin Reuptake Inhibitors