title: Candidate genes expression profile associated with antidepressants response in the GENDEP study: differentiating between baseline 'predictors' and longitudinal 'targets'.
abstract: To improve the 'personalized-medicine' approach to the treatment of depression, we need to identify biomarkers that, assessed before starting treatment, predict future response to antidepressants ('predictors'), as well as biomarkers that are targeted by antidepressants and change longitudinally during the treatment ('targets'). In this study, we tested the leukocyte mRNA expression levels of genes belonging to glucocorticoid receptor (GR) function (FKBP-4, FKBP-5, and GR), inflammation (interleukin (IL)-1α, IL-1β, IL-4, IL-6, IL-7, IL-8, IL-10, macrophage inhibiting factor (MIF), and tumor necrosis factor (TNF)-α), and neuroplasticity (brain-derived neurotrophic factor (BDNF), p11 and VGF), in healthy controls (n=34) and depressed patients (n=74), before and after 8 weeks of treatment with escitalopram or nortriptyline, as part of the Genome-based Therapeutic Drugs for Depression study. Non-responders had higher baseline mRNA levels of IL-1β (+33%), MIF (+48%), and TNF-α (+39%). Antidepressants reduced the levels of IL-1β (-6%) and MIF (-24%), and increased the levels of GR (+5%) and p11 (+8%), but these changes were not associated with treatment response. In contrast, successful antidepressant response was associated with a reduction in the levels of IL-6 (-9%) and of FKBP5 (-11%), and with an increase in the levels of BDNF (+48%) and VGF (+20%)-that is, response was associated with changes in genes that did not predict, at the baseline, the response. Our findings indicate a dissociation between 'predictors' and 'targets' of antidepressant responders. Indeed, while higher levels of proinflammatory cytokines predict lack of future response to antidepressants, changes in inflammation associated with antidepressant response are not reflected by all cytokines at the same time. In contrast, modulation of the GR complex and of neuroplasticity is needed to observe a therapeutic antidepressant effect.
authors.affiliation: Department of Biomedical Sciences and Biotechnology, Genetic and Biology Section, University of Brescia, Brescia, Italy.
authors.forename: Annamaria
authors.initials: A
authors.lastname: Cattaneo
authors.forename: Massimo
authors.initials: M
authors.lastname: Gennarelli
authors.forename: Rudolf
authors.initials: R
authors.lastname: Uher
authors.forename: Gerome
authors.initials: G
authors.lastname: Breen
authors.forename: Anne
authors.initials: A
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: Christoph
authors.initials: C
authors.lastname: Anacker
authors.forename: Patricia A
authors.initials: PA
authors.lastname: Zunsztain
authors.forename: Peter
authors.initials: P
authors.lastname: McGuffin
authors.forename: Carmine M
authors.initials: CM
authors.lastname: Pariante
mesh_terms: D000328:Adult; D000368:Aged; D000928:Antidepressive Agents / Q000008:administration & dosage*; D003866:Depressive Disorder / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D016503:Drug Delivery Systems / Q000379:methods*; D005260:Female; D056726:Genetic Association Studies / Q000379:methods*; D055106:Genome-Wide Association Study / Q000379:methods*; D006801:Humans; D053583:Interleukin-1beta / Q000096:biosynthesis / Q000235:genetics; D019746:Intramolecular Oxidoreductases / Q000096:biosynthesis / Q000235:genetics; D008137:Longitudinal Studies; D008263:Macrophage Migration-Inhibitory Factors / Q000096:biosynthesis / Q000235:genetics; D008297:Male; D008875:Middle Aged; D011237:Predictive Value of Tests; D059467:Transcriptome / Q000187:drug effects / Q000235:genetics*; D016896:Treatment Outcome; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000235:genetics
chemical_list: D000928:Antidepressive Agents; D053583:Interleukin-1beta; D008263:Macrophage Migration-Inhibitory Factors; D014409:Tumor Necrosis Factor-alpha; D019746:Intramolecular Oxidoreductases; C515598:MIF protein, human