title: Tumor necrosis factor and its targets in the inflammatory cytokine pathway are identified as putative transcriptomic biomarkers for escitalopram response.
abstract: Converging evidence suggests that the activation of the inflammatory cytokine pathway is important in the pathophysiology of unipolar depression. Antidepressants have anti-inflammatory properties and evidence suggests that inter-individual variability in response to antidepressants may reflect genetic differences in the inflammatory cytokine pathway. In particular, protein levels of Tumor Necrosis Factor (TNF) and the SNPs rs1126757 in interleukin-11 (IL11), and rs7801617 in interleukin-6 (IL6), have previously been implicated in the clinical response to the selective serotonin reuptake inhibitor (SSRI) antidepressant escitalopram. This study investigated the transcription of TNF, IL11 and IL6 as well as genes in the wider inflammatory cytokine pathway both at baseline and after escitalopram treatment in depressed patients who were either clinical "responders" (n=25) or "non-responders" (n=21). Samples were obtained as a subset of the Genome-Based Therapeutic Drugs for Depression (GENDEP) project and response status is based on changes in the Montgomery-Asberg Depression Rating Scores over a 12 wk treatment period. Binary logistic regressions revealed significant expression differences at baseline between responders and non-responders in TNF, and after escitalopram treatment in TNF and IL11. Differences in IL11 after treatment were found to be driven by drug-induced allele-specific expression differences relating to rs1126757. Top hits in the wider inflammatory cytokine pathway at both baseline and after escitalopram treatment were found to be targets of TNF. The current study adds substantial support for the role of the inflammatory cytokine pathway in mediating response to the SSRI escitalopram, and is the first to identify TNF and its targets as putative transcriptomic predictors of clinical response.
authors.affiliation: King's College London, Institute of Psychiatry, MRC Social, Genetic and Developmental Psychiatry Centre, London, UK. Electronic address: timothy.powell@kcl.ac.uk.
authors.forename: Timothy R
authors.initials: TR
authors.lastname: Powell
authors.forename: Leonard C
authors.initials: LC
authors.lastname: Schalkwyk
authors.forename: Andrew L
authors.initials: AL
authors.lastname: Heffernan
authors.forename: Gerome
authors.initials: G
authors.lastname: Breen
authors.forename: Timothy
authors.initials: T
authors.lastname: Lawrence
authors.forename: Tom
authors.initials: T
authors.lastname: Price
authors.forename: Anne E
authors.initials: AE
authors.lastname: Farmer
authors.forename: Katherine J
authors.initials: KJ
authors.lastname: Aitchison
authors.forename: Ian W
authors.initials: IW
authors.lastname: Craig
authors.forename: Andrea
authors.initials: A
authors.lastname: Danese
authors.forename: Cathryn
authors.initials: C
authors.lastname: Lewis
authors.forename: Peter
authors.initials: P
authors.lastname: McGuffin
authors.forename: Rudolf
authors.initials: R
authors.lastname: Uher
authors.forename: Katherine E
authors.initials: KE
authors.lastname: Tansey
authors.forename: Ursula M
authors.initials: UM
authors.lastname: D'Souza
mesh_terms: D000328:Adult; D000368:Aged; D015415:Biomarkers / Q000378:metabolism; D015283:Citalopram / Q000008:administration & dosage*; D016207:Cytokines / Q000096:biosynthesis / Q000235:genetics*; D003866:Depressive Disorder / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D016503:Drug Delivery Systems / Q000379:methods; D005260:Female; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D010597:Pharmacogenetics / Q000379:methods; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D017367:Selective Serotonin Reuptake Inhibitors / Q000008:administration & dosage; D059467:Transcriptome / Q000502:physiology; D016896:Treatment Outcome; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000235:genetics*; D055815:Young Adult
chemical_list: D015415:Biomarkers; D015283:Citalopram; D016207:Cytokines; D018836:Inflammation Mediators; D017367:Selective Serotonin Reuptake Inhibitors; D014409:Tumor Necrosis Factor-alpha
keywords: Biomarker; Escitalopram; Pharmacogenetic; SSRI; TNF