title: Gene expression and proliferation biomarkers for antidepressant treatment resistance.
abstract: The neurotrophic hypothesis of depression suggests an association between effects on neuroplasticity and clinical response to antidepressant drug therapy. We studied individual variability in antidepressant drug effects on cell proliferation in lymphoblastoid cell lines (LCLs) from n=25 therapy-resistant patients versus n=25 first-line therapy responders from the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study. Furthermore, the variability in gene expression of genes associated with cell proliferation was analyzed for tentative candidate genes for prediction of individual LCL donor's treatment response. Cell proliferation was quantified by EdU (5-ethynyl-2'-deoxyuridine) assays after 21-day incubation of LCLs with fluoxetine (0.5 ng μl-1) and citalopram (0.3 ng μl-1) as developed and described earlier. Gene expression of a panel of candidate genes derived from genome-wide expression analyses of antidepressant effects on cell proliferation of LCLs from the Munich Antidepressant Response Signature (MARS) study was analyzed by real-time PCR. Significant differences in in vitro cell proliferation effects were detected between the group of LCLs from first-line therapy responders and LCLs from treatment-resistant patients. Gene expression analysis of the candidate gene panel revealed and confirmed influence of the candidate genes ABCB1, FZD7 and WNT2B on antidepressant drug resistance. The potential of these genes as tentative biomarkers for antidepressant drug resistance was confirmed. In vitro cell proliferation testing may serve as functional biomarker for individual neuroplasticity effects of antidepressants.
authors.affiliation: Research Division, Federal Institute for Drugs and Medical Devices (BfArM), Bonn, Germany.
authors.forename: J
authors.initials: J
authors.lastname: Breitfeld
authors.affiliation: Research Division, Federal Institute for Drugs and Medical Devices (BfArM), Bonn, Germany.
authors.forename: C
authors.initials: C
authors.lastname: Scholl
authors.affiliation: Research Division, Federal Institute for Drugs and Medical Devices (BfArM), Bonn, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Steffens
authors.affiliation: Washington Behavioral Medicine Associates, LLC, Chevy Chase, MD, USA.
authors.forename: G
authors.initials: G
authors.lastname: Laje
authors.affiliation: Research Division, Federal Institute for Drugs and Medical Devices (BfArM), Bonn, Germany.|Centre for Translational Medicine, University Bonn Medical Faculty, Bonn, Germany.
authors.forename: J C
authors.initials: JC
authors.lastname: Stingl
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000187:drug effects / Q000235:genetics; D000328:Adult; D000928:Antidepressive Agents / Q000494:pharmacology* / Q000627:therapeutic use; D015415:Biomarkers; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects* / Q000235:genetics; D015283:Citalopram / Q000494:pharmacology / Q000627:therapeutic use; D061218:Depressive Disorder, Treatment-Resistant / Q000188:drug therapy / Q000235:genetics*; D005260:Female; D005473:Fluoxetine / Q000494:pharmacology; D051157:Frizzled Receptors / Q000187:drug effects / Q000235:genetics; D006023:Glycoproteins / Q000187:drug effects / Q000235:genetics; D006801:Humans; D066298:In Vitro Techniques; D054503:Lymphoid Progenitor Cells / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D060888:Real-Time Polymerase Chain Reaction; D015238:Sulfotransferases / Q000187:drug effects / Q000235:genetics; D058118:Transcription Factor 7-Like 2 Protein / Q000187:drug effects / Q000235:genetics; D059467:Transcriptome; D051153:Wnt Proteins / Q000187:drug effects / Q000235:genetics
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D000928:Antidepressive Agents; D015415:Biomarkers; C115810:FZD7 protein, human; D051157:Frizzled Receptors; D006023:Glycoproteins; C544894:TCF7L2 protein, human; D058118:Transcription Factor 7-Like 2 Protein; C115496:WNT2B protein, human; D051153:Wnt Proteins; D005473:Fluoxetine; D015283:Citalopram; C479953:SULT4A1 protein, human; D015238:Sulfotransferases