title: The possible role of the kynurenine pathway in adolescent depression with melancholic features.
abstract: BACKGROUND
  Although adolescent major depressive disorder (MDD) is acknowledged to be a heterogeneous disorder, no studies have reported on biological correlates of its clinical subgroups. This study addresses this issue by examining whether adolescent MDD with and without melancholic features (M-MDD and NonM-MDD) have distinct biological features in the kynurenine pathway (KP). The KP is initiated by pro-inflammatory cytokines via induction of the enzyme indoleamine 2,3-dioxygenase (IDO), which degrades tryptophan (TRP) into kynurenine (KYN). KYN is further metabolized into neurotoxins linked to neuronal dysfunction in MDD. Hypotheses were that, compared to healthy controls and to NonM-MDD adolescents, adolescents with M-MDD would exhibit: (i) increased activation of the KP [i.e., increased KYN and KYN/TRP (reflecting IDO activity)]; (ii) greater neurotoxic loads [i.e., increased 3-hydroxyanthranilic acid (3-HAA, neurotoxin) and 3-HAA/KYN (reflecting production of neurotoxins)]; and (iii) decreased TRP. We also examined relationships between severity of MDD and KP metabolites.
  
  
  METHODS
  Subjects were 20 adolescents with M-MDD, 30 adolescents with NonM-MDD, and 22 healthy adolescents. MDD episode duration had to be >or= 6 weeks and Children's Depression Rating Scale-Revised (CDRS-R) scores were >or= 36. Blood samples were collected at AM after an overnight fast and analyzed using high-performance liquid chromatography. Group contrasts relied on analysis of covariance based on ranks, adjusted for age, gender, and CDRS-R scores. Analyses were repeated excluding medicated patients. Fisher's protected least significant difference was used for multiple comparisons.
  
  
  RESULTS
  As hypothesized, KYN/TRP ratios were elevated and TRP concentrations were reduced in adolescents with M-MDD compared to NonM-MDD adolescents (p = .001 and .006, respectively) and to healthy controls (p = .008 and .022, respectively). These findings remained significant when medicated patients were excluded from the analyses. Significant correlations were obtained exclusively in the M-MDD group between KYN and 3-HAA/KYN and CDRS-R.
  
  
  CONCLUSIONS
  Findings support the notion that adolescent M-MDD may represent a biologically distinct clinical syndrome.
authors.affiliation: NYU Child Study Center, Child and Adolescent Psychiatry, New York University School of Medicine, NY 10016, USA. vilma.gabbay@nyumc.org
authors.forename: Vilma
authors.initials: V
authors.lastname: Gabbay
authors.forename: Rachel G
authors.initials: RG
authors.lastname: Klein
authors.forename: Yisrael
authors.initials: Y
authors.lastname: Katz
authors.forename: Sandra
authors.initials: S
authors.lastname: Mendoza
authors.forename: Leah E
authors.initials: LE
authors.lastname: Guttman
authors.forename: Carmen M
authors.initials: CM
authors.lastname: Alonso
authors.forename: James S
authors.initials: JS
authors.lastname: Babb
authors.forename: Glenn S
authors.initials: GS
authors.lastname: Hirsch
authors.forename: Leonard
authors.initials: L
authors.lastname: Liebes
mesh_terms: D015095:3-Hydroxyanthranilic Acid / Q000378:metabolism; D000293:Adolescent; D002648:Child; D016207:Cytokines / Q000097:blood; D003866:Depressive Disorder / Q000175:diagnosis / Q000503:physiopathology* / Q000523:psychology; D003865:Major Depressive Disorder / Q000175:diagnosis / Q000503:physiopathology* / Q000523:psychology; D004790:Enzyme Induction; D005260:Female; D006801:Humans; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000097:blood; D018836:Inflammation Mediators / Q000097:blood; D007737:Kynurenine / Q000097:blood*; D008297:Male; D009498:Neurotoxins / Q000097:blood; D012016:Reference Values; D014364:Tryptophan / Q000097:blood; D055815:Young Adult
chemical_list: D016207:Cytokines; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D018836:Inflammation Mediators; D009498:Neurotoxins; D015095:3-Hydroxyanthranilic Acid; D007737:Kynurenine; D014364:Tryptophan
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