The possible role of the kynurenine pathway in anhedonia in adolescents

Abstract

To address the heterogeneous nature of adolescent major depression (MDD), we investigated anhedonia, a core symptom of MDD. We recently reported activation of the kynurenine pathway (KP), a central neuroimmunological pathway which metabolizes tryptophan (TRP) into kynurenine (KYN) en route to several neurotoxins, in a group of highly anhedonic MDD adolescents. In this study, we aimed to extend our prior work and examine the relationship between KP activity and anhedonia, measured quantitatively, in a group of MDD adolescents and in a combined group of MDD and healthy control adolescents. Thirty-six adolescents with MDD (22 medication-free) and 20 controls were included in the analysis. Anhedonia scores were generated based on clinician- and subject-rated assessments and a semi-structured clinician interview. Blood KP metabolites, collected in the AM after an overnight fast, were measured using high-performance liquid chromatography. The rate-limiting enzyme of the KP, indoleamine 2,3-dioxygenase (IDO), was estimated by the ratio of KYN/TRP. Pearson correlation tests were used to assess correlations between anhedonia scores and KP measures while controlling for MDD severity. IDO activity and anhedonia scores were positively correlated in the group psychotropic medication-free adolescents with MDD (r = 0.42, P = 0.05) and in a combined group of MDD subjects and healthy controls (including medicated patients: r = 0.30, P = 0.02; excluding medicated patients: r = 0.44, P = 0.004). In conclusions, our findings provide further support for the role for the KP, particularly IDO, in anhedonia in adolescent MDD. These results emphasize the importance of dimensional approaches in the investigation of psychiatric disorders.

Fig. 1

Scatter plots indicating partial correlations between IDO activity and anhedonia scores, controlling for CDRS-R scores. a (top) all MDD subjects, r = 0.31, P = 0.06. b (bottom) medication-free MDD subjects, r = 0.42, P = 0.05

Fig. 2

Scatter plots indicating partial correlations between IDO activity and anhedonia scores, controlling for CDRS-R scores. a (top) all subjects, r = 0.30, P = 0.02. b (bottom) all subjects excluding medicated MDD patients, r = 0.44, P = 0.004. Control subjects are indicated by triangles while MDD subjects are indicated by circles. Note that the range of anhedonia scores in HC group was relatively small (0.0–0.14), so the HC subjects appear clustered together in the plots. The appearance of lower IDO activity and anhedonia scores in the MDD group than in the HC group is a consequence of the statistical control for depression severity and does not reflect the uncontrolled range of either measure

Fig. 3

Overview of the proposed model of the kynurenine pathway in anhedonia. Plasma levels of tryptophan (TRP), kynurenine (KYN), 3-hydroxyanthranilic acid (3-HAA), and KYN/TRP ratio (IDO) were assayed in blood samples from depressed and control adolescents. TRP, KYN, and 3-hydroxykynurenine (3-HK) can cross the blood–brain barrier. PFC prefrontal cortex