title: Proliferation rates and gene expression profiles in human lymphoblastoid cell lines from patients with depression characterized in response to antidepressant drug therapy.
abstract: The current therapy success of depressive disorders remains in need of improvement due to low response rates and a delay in symptomatic improvement. Reliable functional biomarkers would be necessary to predict the individual treatment outcome. On the basis of the neurotrophic hypothesis of antidepressant's action, effects of antidepressant drugs on proliferation may serve as tentative individual markers for treatment efficacy. We studied individual differences in antidepressant drug effects on cell proliferation and gene expression in lymphoblastoid cell lines (LCLs) derived from patients treated for depression with documented clinical treatment outcome. Cell proliferation was characterized by EdU (5-ethynyl-2'-deoxyuridine) incorporation assays following a 3-week incubation with therapeutic concentrations of fluoxetine. Genome-wide expression profiling was conducted by microarrays, and candidate genes such as betacellulin-a gene involved in neuronal stem cell regeneration-were validated by quantitative real-time PCR. Ex vivo assessment of proliferation revealed large differences in fluoxetine-induced proliferation inhibition between donor LCLs, but no association with clinical response was observed. Genome-wide expression analyses followed by pathway and gene ontology analyses identified genes with different expression before vs after 21-day incubation with fluoxetine. Significant correlations between proliferation and gene expression of WNT2B, FZD7, TCF7L2, SULT4A1 and ABCB1 (all involved in neurogenesis or brain protection) were also found. Basal gene expression of SULT4A1 (P=0.029), and gene expression fold changes of WNT2B by ex vivo fluoxetine (P=0.025) correlated with clinical response and clinical remission, respectively. Thus, we identified potential gene expression biomarkers eventually being useful as baseline predictors or as longitudinal targets in antidepressant therapy.
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: Research Division, Federal Institute for Drugs and Medical Devices (BfArM), Bonn, Germany.
authors.forename: K
authors.initials: K
authors.lastname: Brandenburg
authors.affiliation: Institute of Clinical Pharmacology and Pharmacology of Natural Products, University of Ulm, Ulm, Germany.
authors.forename: K
authors.initials: K
authors.lastname: Probst-Schendzielorz
authors.affiliation: Institute of Clinical Pharmacology and Pharmacology of Natural Products, University of Ulm, Ulm, Germany.
authors.forename: O
authors.initials: O
authors.lastname: Efimkina
authors.affiliation: Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: D
authors.initials: D
authors.lastname: Gurwitz
authors.affiliation: Max Planck Institute of Psychiatry, Munich, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Ising
authors.affiliation: Max Planck Institute of Psychiatry, Munich, Germany.|HMNC Holding GmbH, Munich, Germany.
authors.forename: F
authors.initials: F
authors.lastname: Holsboer
authors.affiliation: Max Planck Institute of Psychiatry, Munich, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Lucae
authors.affiliation: Research Division, Federal Institute for Drugs and Medical Devices (BfArM), Bonn, Germany.|Center for Translational Medicine, Bonn University Medical School, Bonn, Germany.
authors.forename: J C
authors.initials: JC
authors.lastname: Stingl
mesh_terms: D000328:Adult; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects*; D003866:Depressive Disorder / Q000188:drug therapy* / Q000235:genetics*; D005260:Female; D005473:Fluoxetine / Q000627:therapeutic use*; D015870:Gene Expression / Q000187:drug effects*; D020869:Gene Expression Profiling; D056726:Genetic Association Studies; D055106:Genome-Wide Association Study; D006801:Humans; D008297:Male; D008875:Middle Aged; D016896:Treatment Outcome
chemical_list: D005473:Fluoxetine