The kynurenine pathway in adolescent depression: preliminary findings from a proton MR spectroscopy study

Abstract

Background: Cytokine induction of the enzyme indoleamine 2,3-dioxygenase (IDO) has been implicated in the development of major depressive disorder (MDD). IDO metabolizes tryptophan (TRP) into kynurenine (KYN), thereby decreasing TRP availability to the brain. KYN is further metabolized into several neurotoxins. The aims of this pilot were to examine possible relationships between plasma TRP, KYN, and 3-hydroxyanthranilic acid (3-HAA, neurotoxic metabolite) and striatal total choline (tCho, cell membrane turnover biomarker) in adolescents with MDD. We hypothesized that MDD adolescents would exhibit: i) positive correlations between KYN and 3-HAA and striatal tCho and a negative correlation between TRP and striatal tCho; and, ii) the anticipated correlations would be more pronounced in the melancholic subtype group.

Methods: Fourteen adolescents with MDD (seven with melancholic features) and six healthy controls were enrolled. Minimums of 6 weeks MDD duration and a severity score of 40 on the Children's Depression Rating Scale-Revised were required. All were scanned at 3T with MRI, multi-voxel 3-dimensional, high, 0.75 cm(3), spatial resolution proton magnetic resonance spectroscopic imaging. Striatal tCho concentrations were assessed using phantom replacement. Spearman correlation coefficients were Bonferroni-corrected.

Results: Positive correlations were found only in the melancholic group, between KYN and 3-HAA and tCho in the right caudate (r=0.93, p=0.03) and the left putamen (r=0.96, p=.006), respectively.

Conclusions: These preliminary findings suggest a possible role of the KYN pathway in adolescent melancholic MDD. Larger studies should follow.

Figure 1

Possible neurotoxic consequences of kynurenine pathway activation. TRP, tryptophan; IFN, interferon; IL, interleukin; 3-HK, 3-hydroxykynurenine; 3-HAA, 3-hydroxyanthranilic acid; QUIN, quinolinic acid; KA, kynurenic acid; BBB, blood-brain barrier; NMDA-R, N-methyl-D-aspartate receptor; tCho, Total Choline; GABA, γ-aminobutyric acid.

Figure 2

(Top) Real part of the summed spectra (thin gray line) in the left putamen (circumscribed region b) and right caudate (circumscribed region a) overlaid with their SITools-FITT model functions (dashed black lines) from the 7 melancholic major depressive disorder (MDD) patients (left columns) and 6 healthy controls (right columns). All spectra are on common intensity and frequency scales. Note the regional signal-to-noise-ratios and quality of the fit procedure from which the values for metabolic quantifications with Eq. [1] were obtained. (Bottom) Axial T2-weighted images from an MDD adolescent with melancholic features (left) and a gender- and age-matched control (right), both superimposed with outlines (white line) of the right caudate (a) and left putamen (b) that were used for volumetry and metabolic quantification.

Figure 3

Scatter plots with regression lines characterizing associations of L-kynurenine (KYN) metabolite plasma levels and striatal total choline (tCho), for the seven adolescents with major depressive disorder in the melancholic subgroup. (A) Plasma KYN concentrations (ng/ml) and tCho (mM) in the right caudate (Spearman correlation: r=0.93, p=0.03); (B) plasma 3-hydroxyantranilic acid (3-HAA) concentrations (ng/ml) and tCho (mM) in the left putamen (r=0.96, p=.006); (C) ranks of KYN and right caudate tCho; (D) ranks of 3-HAA and left putamen tCho. All reported p-values are Bonferroni-corrected within domain (x12) two-sided significance levels. Statistical significance was defined as p≤0.05.