title: Absolute Measurements of Macrophage Migration Inhibitory Factor and Interleukin-1-β mRNA Levels Accurately Predict Treatment Response in Depressed Patients.
abstract: Increased levels of inflammation have been associated with a poorer response to antidepressants in several clinical samples, but these findings have had been limited by low reproducibility of biomarker assays across laboratories, difficulty in predicting response probability on an individual basis, and unclear molecular mechanisms.
  
  
  
  Here we measured absolute mRNA values (a reliable quantitation of number of molecules) of Macrophage Migration Inhibitory Factor and interleukin-1β in a previously published sample from a randomized controlled trial comparing escitalopram vs nortriptyline (GENDEP) as well as in an independent, naturalistic replication sample. We then used linear discriminant analysis to calculate mRNA values cutoffs that best discriminated between responders and nonresponders after 12 weeks of antidepressants. As Macrophage Migration Inhibitory Factor and interleukin-1β might be involved in different pathways, we constructed a protein-protein interaction network by the Search Tool for the Retrieval of Interacting Genes/Proteins.
  
  
  
  We identified cutoff values for the absolute mRNA measures that accurately predicted response probability on an individual basis, with positive predictive values and specificity for nonresponders of 100% in both samples (negative predictive value=82% to 85%, sensitivity=52% to 61%). Using network analysis, we identified different clusters of targets for these 2 cytokines, with Macrophage Migration Inhibitory Factor interacting predominantly with pathways involved in neurogenesis, neuroplasticity, and cell proliferation, and interleukin-1β interacting predominantly with pathways involved in the inflammasome complex, oxidative stress, and neurodegeneration.
  
  
  
  We believe that these data provide a clinically suitable approach to the personalization of antidepressant therapy: patients who have absolute mRNA values above the suggested cutoffs could be directed toward earlier access to more assertive antidepressant strategies, including the addition of other antidepressants or antiinflammatory drugs.
authors.affiliation: Stress, Psychiatry and Immunology Laboratory, Department of Psychological Medicine, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom (Drs Cattaneo and Pariante); Biological Psychiatry Unit, IRCCS Fatebenefratelli Institute, Brescia, Italy (Dr Cattaneo); Statistical Service, IRCCS Fatebenefratelli Institute, Brescia, Italy (Dr Ferrari); Genetic Unit, IRCCS Fatebenefratelli Institute Brescia, Italy and Faculty of Psychology, eCampus University, Novedrate, Como, Italy (Dr Bocchio-Chiavetto); Department of Psychiatry, Dalhousie University, Halifax, Nova Scotia, Canada (Dr Uher); The Social, Genetic, and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom (Dr Uher); Department of Pharmacological and Biomolecular Sciences, University of Milan, Milan, Italy (Dr Riva). annamaria.cattaneo@kcl.ac.uk.
authors.forename: Annamaria
authors.initials: A
authors.lastname: Cattaneo
authors.affiliation: Stress, Psychiatry and Immunology Laboratory, Department of Psychological Medicine, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom (Drs Cattaneo and Pariante); Biological Psychiatry Unit, IRCCS Fatebenefratelli Institute, Brescia, Italy (Dr Cattaneo); Statistical Service, IRCCS Fatebenefratelli Institute, Brescia, Italy (Dr Ferrari); Genetic Unit, IRCCS Fatebenefratelli Institute Brescia, Italy and Faculty of Psychology, eCampus University, Novedrate, Como, Italy (Dr Bocchio-Chiavetto); Department of Psychiatry, Dalhousie University, Halifax, Nova Scotia, Canada (Dr Uher); The Social, Genetic, and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom (Dr Uher); Department of Pharmacological and Biomolecular Sciences, University of Milan, Milan, Italy (Dr Riva).
authors.forename: Clarissa
authors.initials: C
authors.lastname: Ferrari
authors.affiliation: Stress, Psychiatry and Immunology Laboratory, Department of Psychological Medicine, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom (Drs Cattaneo and Pariante); Biological Psychiatry Unit, IRCCS Fatebenefratelli Institute, Brescia, Italy (Dr Cattaneo); Statistical Service, IRCCS Fatebenefratelli Institute, Brescia, Italy (Dr Ferrari); Genetic Unit, IRCCS Fatebenefratelli Institute Brescia, Italy and Faculty of Psychology, eCampus University, Novedrate, Como, Italy (Dr Bocchio-Chiavetto); Department of Psychiatry, Dalhousie University, Halifax, Nova Scotia, Canada (Dr Uher); The Social, Genetic, and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom (Dr Uher); Department of Pharmacological and Biomolecular Sciences, University of Milan, Milan, Italy (Dr Riva).
authors.forename: Rudolf
authors.initials: R
authors.lastname: Uher
authors.affiliation: Stress, Psychiatry and Immunology Laboratory, Department of Psychological Medicine, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom (Drs Cattaneo and Pariante); Biological Psychiatry Unit, IRCCS Fatebenefratelli Institute, Brescia, Italy (Dr Cattaneo); Statistical Service, IRCCS Fatebenefratelli Institute, Brescia, Italy (Dr Ferrari); Genetic Unit, IRCCS Fatebenefratelli Institute Brescia, Italy and Faculty of Psychology, eCampus University, Novedrate, Como, Italy (Dr Bocchio-Chiavetto); Department of Psychiatry, Dalhousie University, Halifax, Nova Scotia, Canada (Dr Uher); The Social, Genetic, and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom (Dr Uher); Department of Pharmacological and Biomolecular Sciences, University of Milan, Milan, Italy (Dr Riva).
authors.forename: Luisella
authors.initials: L
authors.lastname: Bocchio-Chiavetto
authors.affiliation: Stress, Psychiatry and Immunology Laboratory, Department of Psychological Medicine, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom (Drs Cattaneo and Pariante); Biological Psychiatry Unit, IRCCS Fatebenefratelli Institute, Brescia, Italy (Dr Cattaneo); Statistical Service, IRCCS Fatebenefratelli Institute, Brescia, Italy (Dr Ferrari); Genetic Unit, IRCCS Fatebenefratelli Institute Brescia, Italy and Faculty of Psychology, eCampus University, Novedrate, Como, Italy (Dr Bocchio-Chiavetto); Department of Psychiatry, Dalhousie University, Halifax, Nova Scotia, Canada (Dr Uher); The Social, Genetic, and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom (Dr Uher); Department of Pharmacological and Biomolecular Sciences, University of Milan, Milan, Italy (Dr Riva).
authors.forename: Marco Andrea
authors.initials: MA
authors.lastname: Riva
authors.affiliation: Stress, Psychiatry and Immunology Laboratory, Department of Psychological Medicine, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom (Drs Cattaneo and Pariante); Biological Psychiatry Unit, IRCCS Fatebenefratelli Institute, Brescia, Italy (Dr Cattaneo); Statistical Service, IRCCS Fatebenefratelli Institute, Brescia, Italy (Dr Ferrari); Genetic Unit, IRCCS Fatebenefratelli Institute Brescia, Italy and Faculty of Psychology, eCampus University, Novedrate, Como, Italy (Dr Bocchio-Chiavetto); Department of Psychiatry, Dalhousie University, Halifax, Nova Scotia, Canada (Dr Uher); The Social, Genetic, and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom (Dr Uher); Department of Pharmacological and Biomolecular Sciences, University of Milan, Milan, Italy (Dr Riva).
authors.forename: Carmine M
authors.initials: CM
authors.lastname: Pariante
mesh_terms: D000328:Adult; D000339:Affect / Q000187:drug effects*; D018687:Antidepressive Agents, Second-Generation / Q000627:therapeutic use*; D000929:Antidepressive Agents, Tricyclic / Q000627:therapeutic use*; D000073888:Cell-Free Nucleic Acids / Q000097:blood / Q000235:genetics*; D015283:Citalopram / Q000627:therapeutic use*; D003865:Major Depressive Disorder / Q000175:diagnosis / Q000188:drug therapy* / Q000235:genetics / Q000523:psychology; D016002:Discriminant Analysis; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods; D006801:Humans; D053583:Interleukin-1beta / Q000097:blood / Q000235:genetics*; D019746:Intramolecular Oxidoreductases / Q000097:blood / Q000235:genetics*; D016014:Linear Models; D016015:Logistic Models; D008263:Macrophage Migration-Inhibitory Factors / Q000097:blood / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D009661:Nortriptyline / Q000627:therapeutic use*; D011237:Predictive Value of Tests; D060066:Protein Interaction Maps; D012333:RNA, Messenger / Q000097:blood / Q000235:genetics*; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D018687:Antidepressive Agents, Second-Generation; D000929:Antidepressive Agents, Tricyclic; D000073888:Cell-Free Nucleic Acids; C508585:IL1B protein, human; D053583:Interleukin-1beta; D008263:Macrophage Migration-Inhibitory Factors; D012333:RNA, Messenger; D015283:Citalopram; D009661:Nortriptyline; D019746:Intramolecular Oxidoreductases; C515598:MIF protein, human
keywords: cytokine absolute blood levels; personalized medicine; predictors; treatment response