title: Reduced kynurenine pathway metabolism and cytokine expression in the prefrontal cortex of depressed individuals.
abstract: Neuroinflammatory processes are increasingly believed to participate in the pathophysiology of a number of major psychiatric diseases, including depression. Immune activation stimulates the conversion of the amino acid tryptophan to kynurenine, leading to the formation of neuroactive metabolites, such as quinolinic acid and kynurenic acid. These compounds affect glutamatergic neurotransmission, which plays a prominent role in depressive pathology. Increased tryptophan degradation along the kynurenine pathway (KP) has been proposed to contribute to disease etiology.
  
  
  
  We used postmortem brain tissue from the ventrolateral prefrontal cortex (VLPFC) to assess tissue levels of tryptophan and KP metabolites, the expression of several KP enzymes and a series of cytokines as well as tissue pathology, including microglial activation. Tissue samples came from nonpsychiatric controls (n= 36) and individuals with depressive disorder not otherwise specified (DD-NOS,n= 45) who died of natural causes, homicide, accident, or suicide.
  
  
  
  We found a reduction in the enzymatic conversion of tryptophan to kynurenine, determined using the kynurenine:tryptophan ratio, and reduced messenger RNA expression of the enzymes indoleamine-2,3-dioxygenase 1 and 2 and tryptophan-2,3-dioxygenase in depressed individuals irrespective of the cause of death. These findings correlated with reductions in the expression of several cytokines, including interferon-γ and tumour necrosis factor-α. Notably, quinolinic acid levels were also lower in depressed individuals than controls.
  
  
  
  Information on the use of antidepressants and other psychotropic medications was insufficient for statistical comparisons.
  
  
  
  Contrary to expectations, the present results indicate that depression, in the absence of medical illness or an overt inflammatory process, is associated with compromised, rather than increased, KP metabolism in the VLPFC.
authors.affiliation: From the Laboratory of Behavioral Neuroimmunology, Department of Psychiatry, University of Maryland School of Medicine, Baltimore, MD (Clark, Nicholson, Tonelli); the Maryland Psychiatric Research Center, Department of Psychiatry, University of Maryland School of Medicine, Baltimore, MD (Pocivavsek, Notarangelo, McMahon, Schwarcz); the Department of Epidemiology and Public Health, University of Maryland School of Medicine, Baltimore, MD (Langenberg); the Section on Neuropathology, Clinical Brain Disorders Branch, Division of Intramural Research Programs, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland (Kleinman, Hyde); the Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, MD (Kleinman, Hyde); and the Mood and Anxiety Program, Department of Psychiatry, University of Maryland School of Medicine, Baltimore, MD (Stiller, Postolache).
authors.forename: Sarah M
authors.initials: SM
authors.lastname: Clark
authors.affiliation: From the Laboratory of Behavioral Neuroimmunology, Department of Psychiatry, University of Maryland School of Medicine, Baltimore, MD (Clark, Nicholson, Tonelli); the Maryland Psychiatric Research Center, Department of Psychiatry, University of Maryland School of Medicine, Baltimore, MD (Pocivavsek, Notarangelo, McMahon, Schwarcz); the Department of Epidemiology and Public Health, University of Maryland School of Medicine, Baltimore, MD (Langenberg); the Section on Neuropathology, Clinical Brain Disorders Branch, Division of Intramural Research Programs, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland (Kleinman, Hyde); the Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, MD (Kleinman, Hyde); and the Mood and Anxiety Program, Department of Psychiatry, University of Maryland School of Medicine, Baltimore, MD (Stiller, Postolache).
authors.forename: Ana
authors.initials: A
authors.lastname: Pocivavsek
authors.affiliation: From the Laboratory of Behavioral Neuroimmunology, Department of Psychiatry, University of Maryland School of Medicine, Baltimore, MD (Clark, Nicholson, Tonelli); the Maryland Psychiatric Research Center, Department of Psychiatry, University of Maryland School of Medicine, Baltimore, MD (Pocivavsek, Notarangelo, McMahon, Schwarcz); the Department of Epidemiology and Public Health, University of Maryland School of Medicine, Baltimore, MD (Langenberg); the Section on Neuropathology, Clinical Brain Disorders Branch, Division of Intramural Research Programs, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland (Kleinman, Hyde); the Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, MD (Kleinman, Hyde); and the Mood and Anxiety Program, Department of Psychiatry, University of Maryland School of Medicine, Baltimore, MD (Stiller, Postolache).
authors.forename: James D
authors.initials: JD
authors.lastname: Nicholson
authors.affiliation: From the Laboratory of Behavioral Neuroimmunology, Department of Psychiatry, University of Maryland School of Medicine, Baltimore, MD (Clark, Nicholson, Tonelli); the Maryland Psychiatric Research Center, Department of Psychiatry, University of Maryland School of Medicine, Baltimore, MD (Pocivavsek, Notarangelo, McMahon, Schwarcz); the Department of Epidemiology and Public Health, University of Maryland School of Medicine, Baltimore, MD (Langenberg); the Section on Neuropathology, Clinical Brain Disorders Branch, Division of Intramural Research Programs, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland (Kleinman, Hyde); the Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, MD (Kleinman, Hyde); and the Mood and Anxiety Program, Department of Psychiatry, University of Maryland School of Medicine, Baltimore, MD (Stiller, Postolache).
authors.forename: Francesca M
authors.initials: FM
authors.lastname: Notarangelo
authors.affiliation: From the Laboratory of Behavioral Neuroimmunology, Department of Psychiatry, University of Maryland School of Medicine, Baltimore, MD (Clark, Nicholson, Tonelli); the Maryland Psychiatric Research Center, Department of Psychiatry, University of Maryland School of Medicine, Baltimore, MD (Pocivavsek, Notarangelo, McMahon, Schwarcz); the Department of Epidemiology and Public Health, University of Maryland School of Medicine, Baltimore, MD (Langenberg); the Section on Neuropathology, Clinical Brain Disorders Branch, Division of Intramural Research Programs, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland (Kleinman, Hyde); the Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, MD (Kleinman, Hyde); and the Mood and Anxiety Program, Department of Psychiatry, University of Maryland School of Medicine, Baltimore, MD (Stiller, Postolache).
authors.forename: Patricia
authors.initials: P
authors.lastname: Langenberg
authors.affiliation: From the Laboratory of Behavioral Neuroimmunology, Department of Psychiatry, University of Maryland School of Medicine, Baltimore, MD (Clark, Nicholson, Tonelli); the Maryland Psychiatric Research Center, Department of Psychiatry, University of Maryland School of Medicine, Baltimore, MD (Pocivavsek, Notarangelo, McMahon, Schwarcz); the Department of Epidemiology and Public Health, University of Maryland School of Medicine, Baltimore, MD (Langenberg); the Section on Neuropathology, Clinical Brain Disorders Branch, Division of Intramural Research Programs, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland (Kleinman, Hyde); the Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, MD (Kleinman, Hyde); and the Mood and Anxiety Program, Department of Psychiatry, University of Maryland School of Medicine, Baltimore, MD (Stiller, Postolache).
authors.forename: Robert P
authors.initials: RP
authors.lastname: McMahon
authors.affiliation: From the Laboratory of Behavioral Neuroimmunology, Department of Psychiatry, University of Maryland School of Medicine, Baltimore, MD (Clark, Nicholson, Tonelli); the Maryland Psychiatric Research Center, Department of Psychiatry, University of Maryland School of Medicine, Baltimore, MD (Pocivavsek, Notarangelo, McMahon, Schwarcz); the Department of Epidemiology and Public Health, University of Maryland School of Medicine, Baltimore, MD (Langenberg); the Section on Neuropathology, Clinical Brain Disorders Branch, Division of Intramural Research Programs, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland (Kleinman, Hyde); the Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, MD (Kleinman, Hyde); and the Mood and Anxiety Program, Department of Psychiatry, University of Maryland School of Medicine, Baltimore, MD (Stiller, Postolache).
authors.forename: Joel E
authors.initials: JE
authors.lastname: Kleinman
authors.affiliation: From the Laboratory of Behavioral Neuroimmunology, Department of Psychiatry, University of Maryland School of Medicine, Baltimore, MD (Clark, Nicholson, Tonelli); the Maryland Psychiatric Research Center, Department of Psychiatry, University of Maryland School of Medicine, Baltimore, MD (Pocivavsek, Notarangelo, McMahon, Schwarcz); the Department of Epidemiology and Public Health, University of Maryland School of Medicine, Baltimore, MD (Langenberg); the Section on Neuropathology, Clinical Brain Disorders Branch, Division of Intramural Research Programs, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland (Kleinman, Hyde); the Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, MD (Kleinman, Hyde); and the Mood and Anxiety Program, Department of Psychiatry, University of Maryland School of Medicine, Baltimore, MD (Stiller, Postolache).
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Hyde
authors.affiliation: From the Laboratory of Behavioral Neuroimmunology, Department of Psychiatry, University of Maryland School of Medicine, Baltimore, MD (Clark, Nicholson, Tonelli); the Maryland Psychiatric Research Center, Department of Psychiatry, University of Maryland School of Medicine, Baltimore, MD (Pocivavsek, Notarangelo, McMahon, Schwarcz); the Department of Epidemiology and Public Health, University of Maryland School of Medicine, Baltimore, MD (Langenberg); the Section on Neuropathology, Clinical Brain Disorders Branch, Division of Intramural Research Programs, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland (Kleinman, Hyde); the Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, MD (Kleinman, Hyde); and the Mood and Anxiety Program, Department of Psychiatry, University of Maryland School of Medicine, Baltimore, MD (Stiller, Postolache).
authors.forename: John
authors.initials: J
authors.lastname: Stiller
authors.affiliation: From the Laboratory of Behavioral Neuroimmunology, Department of Psychiatry, University of Maryland School of Medicine, Baltimore, MD (Clark, Nicholson, Tonelli); the Maryland Psychiatric Research Center, Department of Psychiatry, University of Maryland School of Medicine, Baltimore, MD (Pocivavsek, Notarangelo, McMahon, Schwarcz); the Department of Epidemiology and Public Health, University of Maryland School of Medicine, Baltimore, MD (Langenberg); the Section on Neuropathology, Clinical Brain Disorders Branch, Division of Intramural Research Programs, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland (Kleinman, Hyde); the Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, MD (Kleinman, Hyde); and the Mood and Anxiety Program, Department of Psychiatry, University of Maryland School of Medicine, Baltimore, MD (Stiller, Postolache).
authors.forename: Teodor T
authors.initials: TT
authors.lastname: Postolache
authors.affiliation: From the Laboratory of Behavioral Neuroimmunology, Department of Psychiatry, University of Maryland School of Medicine, Baltimore, MD (Clark, Nicholson, Tonelli); the Maryland Psychiatric Research Center, Department of Psychiatry, University of Maryland School of Medicine, Baltimore, MD (Pocivavsek, Notarangelo, McMahon, Schwarcz); the Department of Epidemiology and Public Health, University of Maryland School of Medicine, Baltimore, MD (Langenberg); the Section on Neuropathology, Clinical Brain Disorders Branch, Division of Intramural Research Programs, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland (Kleinman, Hyde); the Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, MD (Kleinman, Hyde); and the Mood and Anxiety Program, Department of Psychiatry, University of Maryland School of Medicine, Baltimore, MD (Stiller, Postolache).
authors.forename: Robert
authors.initials: R
authors.lastname: Schwarcz
authors.affiliation: From the Laboratory of Behavioral Neuroimmunology, Department of Psychiatry, University of Maryland School of Medicine, Baltimore, MD (Clark, Nicholson, Tonelli); the Maryland Psychiatric Research Center, Department of Psychiatry, University of Maryland School of Medicine, Baltimore, MD (Pocivavsek, Notarangelo, McMahon, Schwarcz); the Department of Epidemiology and Public Health, University of Maryland School of Medicine, Baltimore, MD (Langenberg); the Section on Neuropathology, Clinical Brain Disorders Branch, Division of Intramural Research Programs, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland (Kleinman, Hyde); the Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, MD (Kleinman, Hyde); and the Mood and Anxiety Program, Department of Psychiatry, University of Maryland School of Medicine, Baltimore, MD (Stiller, Postolache).
authors.forename: Leonardo H
authors.initials: LH
authors.lastname: Tonelli
mesh_terms: D000328:Adult; D016207:Cytokines / Q000378:metabolism*; D003866:Depressive Disorder / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D007737:Kynurenine / Q000378:metabolism*; D008297:Male; D016133:Polymerase Chain Reaction; D017397:Prefrontal Cortex / Q000378:metabolism* / Q000473:pathology; D012333:RNA, Messenger / Q000378:metabolism
chemical_list: D016207:Cytokines; D012333:RNA, Messenger; D007737:Kynurenine