title: Circulating cytotoxic T cells and natural killer cells as potential predictors for antidepressant response in melancholic depression. Restoration of T regulatory cell populations after antidepressant therapy.
abstract: BACKGROUND
  There is a substantial unmet need for biomarkers to predict treatment response in major depressive disorder (MDD). Evidence has converged on activation of the inflammatory response system as a fundamental mechanism underlying MDD.
  
  
  OBJECTIVE
  By investigating circulating leukocyte subsets quantified by fluorescence-activated cell sorting (FACS) analysis before treatment, we aim to predict antidepressant response.
  
  
  METHODS
  Forty medication-free inpatients with melancholic, non-psychotic depression before treatment with either venlafaxine or imipramine and 40 age- and gender-matched healthy controls were included. Leukocyte subsets were quantified by FACS analysis using frozen peripheral blood mononuclear cells (PBMC) collected prior to and after 7 weeks of treatment with either venlafaxine (375 mg/day) or imipramine (blood level 200-300 ng/ml). Response was defined as at least 50 % reduction of the baseline Hamilton Rating Scale for Depression (HAM-D) score.
  
  
  RESULTS
  Prior to treatment, MDD patients showed reduced percentages of CD4(+)CD25(high)Foxp3(+) T regulatory (Treg) cells when compared with controls (1.5 ± 0.6 vs. 1.8 ± 0.6, p = .037). After treatment, robust rises in Treg cells were observed in patients (1.8 ± 0.7, p < .001), yet Treg cells were not predictors of the clinical outcome of treatment. Antidepressant non-responders showed increased CD8(+) cytotoxic T cell percentages (24.0 ± 8.6 vs. 15.9 ± 5.9, p = .004) and decreased natural killer (NK) cell percentages (14.0 ± 6.9 vs. 21.4 ± 11.9, p = .020) compared with responders before treatment. Both lymphocyte levels were not significantly modulated by treatment.
  
  
  CONCLUSIONS
  In melancholic MDD, FACS analysis of circulating leukocyte subpopulations might help to discriminate between patients with high or low responsiveness to antidepressant treatment.
authors.affiliation: Department of Immunology, Erasmus Medical Center, Wijtemaweg 80, 3015CN, Rotterdam, The Netherlands. laura.grosse@ukmuenster.de.|Department of Psychiatry, University of Muenster, Muenster, Germany. laura.grosse@ukmuenster.de.
authors.forename: Laura
authors.initials: L
authors.lastname: Grosse
authors.affiliation: Department of Epidemiology and Public Health, University College London, London, UK.
authors.forename: Livia A
authors.initials: LA
authors.lastname: Carvalho
authors.affiliation: Department of Psychiatry, Erasmus Medical Center, Rotterdam, The Netherlands.
authors.forename: Tom K
authors.initials: TK
authors.lastname: Birkenhager
authors.affiliation: Department of Psychiatry, Erasmus Medical Center, Rotterdam, The Netherlands.
authors.forename: Witte J
authors.initials: WJ
authors.lastname: Hoogendijk
authors.affiliation: Department of Psychiatry, Erasmus Medical Center, Rotterdam, The Netherlands.
authors.forename: Steven A
authors.initials: SA
authors.lastname: Kushner
authors.affiliation: Department of Immunology, Erasmus Medical Center, Wijtemaweg 80, 3015CN, Rotterdam, The Netherlands.
authors.forename: Hemmo A
authors.initials: HA
authors.lastname: Drexhage
authors.affiliation: Department of Psychiatry, Erasmus Medical Center, Rotterdam, The Netherlands.
authors.forename: Veerle
authors.initials: V
authors.lastname: Bergink
mesh_terms: D000328:Adult; D000928:Antidepressive Agents / Q000627:therapeutic use*; D018687:Antidepressive Agents, Second-Generation / Q000627:therapeutic use; D000929:Antidepressive Agents, Tricyclic / Q000627:therapeutic use; D003865:Major Depressive Disorder / Q000188:drug therapy* / Q000276:immunology*; D039721:Diagnostic and Statistical Manual of Mental Disorders; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D007099:Imipramine / Q000627:therapeutic use; D007694:Killer Cells, Natural / Q000276:immunology*; D018655:Lymphocyte Count; D008297:Male; D008875:Middle Aged; D011237:Predictive Value of Tests; D011569:Psychiatric Status Rating Scales; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D016896:Treatment Outcome; D000069470:Venlafaxine Hydrochloride / Q000627:therapeutic use
chemical_list: D000928:Antidepressive Agents; D018687:Antidepressive Agents, Second-Generation; D000929:Antidepressive Agents, Tricyclic; D000069470:Venlafaxine Hydrochloride; D007099:Imipramine
keywords: Antidepressants; Cytotoxic T cells; Fluorescence-activated cell sorting; Major depressive disorder; Natural killer cells; T regulatory cells; Treatment reponse