title: Whole-genome expression analysis reveals genes associated with treatment response to escitalopram in major depression.
abstract: The reasons for variability in treatment response in major depressive disorder (MDD) are not fully understood, but there is accumulating evidence suggesting that therapeutic outcomes of antidepressants can be influenced by genetic factors. In the present study we applied the microarray Illumina platform for whole genome expression profiling in depressive patients treated with escitalopram medication in order to identify genes underlying response to antidepressant treatment. The initial study sample consisted of 135 outpatients with major depressive disorder (mean age 31.1±11.6 years, 68% females) treated with escitalopram 10-20mg/day for 12 weeks, from which 87 patients (55 females) were included in gene expression analyzing. The gene expression profiles were measured on peripheral blood cells at baseline, at week 4 and at the end of treatment (week 12) using BeadChips Illumina. The fold change was used to demonstrate rate of changes in average gene expressions between studied groups. Statistical analyses were performed using the false discovery rate (FDR). The most interesting gene, which showed the predictive effect on treatment outcome by delineating low dose responders and treatment-resistant patients at the beginning of medication, was NLGN2, belonging to a family of neuronal cell surface proteins and involving in synapse formation. In addition, the several gene clusters, related to immune response, signal transduction and neurotrophin pathway, have distinguished responders from non-responders at the week 4 of treatment. After 4 weeks of escitalopram treatment (10mg/day), the YWHAZ gene has showed the highest transcriptional change in responders as compared with non-responders. Finally, at the end of the treatment we noticed that at least three genes (NR2C2, ZNF641, FKBP1A) have been strongly associated with resistance to escitalopram. Thus the results of this study support that exploration of peripheral gene expression is a useful tool in the further identification of novel genetic biomarkers for antidepressant treatment response.
authors.affiliation: Estonian Genome Center, University of Tartu, Estonia.
authors.forename: Kristi
authors.initials: K
authors.lastname: Pettai
authors.affiliation: Estonian Genome Center, University of Tartu, Estonia.
authors.forename: Lili
authors.initials: L
authors.lastname: Milani
authors.affiliation: Estonian Genome Center, University of Tartu, Estonia.
authors.forename: Anu
authors.initials: A
authors.lastname: Tammiste
authors.affiliation: Estonian Genome Center, University of Tartu, Estonia.
authors.forename: Urmo
authors.initials: U
authors.lastname: Võsa
authors.affiliation: Institute of Computer Science, University of Tartu, Estonia; Quretec, Tartu, Estonia.
authors.forename: Raivo
authors.initials: R
authors.lastname: Kolde
authors.affiliation: Department of Psychiatry, University of Tartu, Tartu, Estonia.
authors.forename: Triin
authors.initials: T
authors.lastname: Eller
authors.affiliation: Centre for Neuropsychopharmacology Imperial College London, London, UK.
authors.forename: David
authors.initials: D
authors.lastname: Nutt
authors.affiliation: Estonian Genome Center, University of Tartu, Estonia; Institute of Molecular and Cell Biology, University of Tartu, Estonia.
authors.forename: Andres
authors.initials: A
authors.lastname: Metspalu
authors.affiliation: Department of Psychiatry, University of Tartu, Tartu, Estonia; Centre for Neuropsychopharmacology Imperial College London, London, UK; Research and Development Service and Department of Psychiatry, North Estonia Medical Centre, Tallinn, Estonia. Electronic address: e.maron@imperial.ac.uk.
authors.forename: Eduard
authors.initials: E
authors.lastname: Maron
mesh_terms: D000328:Adult; D018687:Antidepressive Agents, Second-Generation / Q000627:therapeutic use*; D015283:Citalopram / Q000627:therapeutic use*; D003865:Major Depressive Disorder / Q000188:drug therapy* / Q000235:genetics*; D005260:Female; D020869:Gene Expression Profiling; D016678:Genome; D006801:Humans; D008297:Male; D046228:Microarray Analysis; D011569:Psychiatric Status Rating Scales; D011987:Receptors, Steroid / Q000235:genetics; D011988:Receptors, Thyroid Hormone / Q000235:genetics; D022021:Tacrolimus Binding Proteins / Q000235:genetics; D015534:Trans-Activators / Q000235:genetics; D016896:Treatment Outcome
chemical_list: D018687:Antidepressive Agents, Second-Generation; C550432:FKBP1A protein, human; C490515:NR2C2 protein, human; D011987:Receptors, Steroid; D011988:Receptors, Thyroid Hormone; D015534:Trans-Activators; C508078:ZNF641 protein, human; D015283:Citalopram; D022021:Tacrolimus Binding Proteins
keywords: Escitalopram; Gene expression; Major depression; SSRI; Treatment prediction