title: Decreased sensitivity to paroxetine-induced inhibition of peripheral blood mononuclear cell growth in depressed and antidepressant treatment-resistant patients.
abstract: Major depression disorder (MDD) is the most widespread mental disorder. Selective serotonin reuptake inhibitors (SSRIs) are used as first-line MDD treatment but are effective in <70% of patients. Thus, biomarkers for the early identification of treatment-resistant (TR) MDD patients are needed for prioritizing them for alternative therapeutics. SSRI-induced inhibition of the growth of peripheral blood mononuclear cells (PBMCs) is mediated via their target, the serotonin transporter (SERT). Here, we examined whether antidepressant drug-induced inhibition of the growth of PBMCs differed between MDD patients and healthy controls. PBMCs from well-characterized 33 treatment-sensitive (TS) and 33 TR MDD patients, and 24 healthy volunteers were studied. Dose-dependent inhibition of PBMCs growth was observed for both the non-SSRI antidepressant mirtazapine and the SSRI antidepressant paroxetine. Significantly lower sensitivities to 20 μm paroxetine were observed in MDD compared with control PBMCs prior to treatment onset (13% and 46%, respectively; P<0.05). Following antidepressant drug treatment for 4 or 7 weeks, the ex vivo paroxetine sensitivity increased to control levels in PBMCs from TS but not from TR MDD patients. This suggests that the low ex vivo paroxetine sensitivity phenotype reflects a state marker of depression. A significantly lower expression of integrin beta-3 (ITGB3), a co-factor of the SERT, was observed in the PBMCs of MDD patients prior to treatment onset compared with healthy controls, and may explain their lower paroxetine sensitivity. Further studies with larger cohorts are required for clarifying the potential of reduced PBMCs paroxetine sensitivity and lower ITGB3 expression as MDD biomarkers.
authors.affiliation: Department of Neurobiology, Institute of Pharmacology Polish Academy of Science, Krakow, Poland.
authors.forename: S
authors.initials: S
authors.lastname: Rzezniczek
authors.affiliation: Department of Neurobiology, Institute of Pharmacology Polish Academy of Science, Krakow, Poland.
authors.forename: M
authors.initials: M
authors.lastname: Obuchowicz
authors.affiliation: Department of Affective Disorders, Chair of Psychiatry, Jagiellonian University Medical College, Krakow, Poland.
authors.forename: W
authors.initials: W
authors.lastname: Datka
authors.affiliation: Department of Affective Disorders, Chair of Psychiatry, Jagiellonian University Medical College, Krakow, Poland.
authors.forename: M
authors.initials: M
authors.lastname: Siwek
authors.affiliation: Department of Affective Disorders, Chair of Psychiatry, Jagiellonian University Medical College, Krakow, Poland.
authors.forename: D
authors.initials: D
authors.lastname: Dudek
authors.affiliation: Department of Affective Disorders, Chair of Psychiatry, Jagiellonian University Medical College, Krakow, Poland.
authors.forename: K
authors.initials: K
authors.lastname: Kmiotek
authors.affiliation: Department of Human Molecular Genetics & Biochemistry, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.|Department of Cell and Developmental Biology, Tel Aviv University, Sackler Faculty of Medicine, Tel Aviv, Israel.
authors.forename: K
authors.initials: K
authors.lastname: Oved
authors.affiliation: Department of Cell and Developmental Biology, Tel Aviv University, Sackler Faculty of Medicine, Tel Aviv, Israel.|Sagol School of Neuroscience, Tel Aviv University, Tel Aviv, Israel.
authors.forename: N
authors.initials: N
authors.lastname: Shomron
authors.affiliation: Department of Human Molecular Genetics & Biochemistry, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.|Sagol School of Neuroscience, Tel Aviv University, Tel Aviv, Israel.
authors.forename: D
authors.initials: D
authors.lastname: Gurwitz
authors.affiliation: Department of Neurobiology, Institute of Pharmacology Polish Academy of Science, Krakow, Poland.|Institute of Public Health, Faculty of Health Sciences, Jagiellonian University, Krakow, Poland.
authors.forename: A
authors.initials: A
authors.lastname: Pilc
mesh_terms: D000328:Adult; D015415:Biomarkers; D049109:Cell Proliferation / Q000187:drug effects; D003865:Major Depressive Disorder / Q000188:drug therapy* / Q000235:genetics; D061218:Depressive Disorder, Treatment-Resistant / Q000188:drug therapy* / Q000235:genetics; D005260:Female; D006801:Humans; D039661:Integrin beta3 / Q000235:genetics; D008297:Male; D008803:Mianserin / Q000031:analogs & derivatives* / Q000627:therapeutic use; D008875:Middle Aged; D000078785:Mirtazapine; D009000:Monocytes / Q000187:drug effects*; D017374:Paroxetine / Q000627:therapeutic use*; D010446:Peptide Fragments; D050486:Serotonin Plasma Membrane Transport Proteins / Q000187:drug effects*
chemical_list: D015415:Biomarkers; D039661:Integrin beta3; D010446:Peptide Fragments; D050486:Serotonin Plasma Membrane Transport Proteins; C073659:glycoprotein IIIa-derived peptide (217-231); D008803:Mianserin; D017374:Paroxetine; D000078785:Mirtazapine