Conflict of interest statement: Dr. Vilma Gabbay serves as a Sub-Investigator on a study sponsored by Boehringer Ingelheim and Otsuka Pharmaceuticals, but has received no compensation for this work. At the time of data collection, Dr. Babb had consulting contracts with E-Z-EM, Inc. and Applied NeuroSolutions, Inc, but received no compensation over the last three years for these services and has since allowed all such contracts to expire. Drs. Klein, Alonso, Hirsch and Liebes, and Sandra Mendoza, Yisrael Katz and Leah E. Guttman report no conflicts of interest.
The possible role of the kynurenine pathway in adolescent depression with melancholic features
Version of Record online: 12 APR 2010
© 2010 The Authors. Journal compilation © 2010 Association for Child and Adolescent Mental Health
Journal of Child Psychology and Psychiatry
Volume 51, Issue 8, pages 935–943, August 2010
How to Cite
Gabbay, V., Klein, R. G., Katz, Y., Mendoza, S., Guttman, L. E., Alonso, C. M., Babb, J. S., Hirsch, G. S. and Liebes, L. (2010), The possible role of the kynurenine pathway in adolescent depression with melancholic features. Journal of Child Psychology and Psychiatry, 51: 935–943. doi: 10.1111/j.1469-7610.2010.02245.x
- Issue online: 9 JUL 2010
- Version of Record online: 12 APR 2010
- Manuscript accepted 18 February 2010
- Adolescent depression;
- kynurenine (KYN);
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 ≥ 6 weeks and Children’s Depression Rating Scale-Revised (CDRS-R) scores were ≥ 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.