Sex-Specific Alterations of the Kynurenine Pathway in Association With Risk for and Remission of Depression in Adolescence
Naghmeh Nikkheslat, Zuzanna Zajkowska, Cristina Legido‐Quigley, Jin Xu, Pedro H. Manfro, Laila Souza, Rivka Pereira, Fernanda Rohrsetzer, Jader Piccin, Anna Viduani, Brandon A. Kohrt, Helen L. Fisher, Christian Kieling, Valeria Mondelli
Abstract
BACKGROUND: The imbalance between neurotoxic and neuroprotective metabolites of the kynurenine pathway has been implicated in the pathophysiology of major depressive disorder (MDD) in adulthood but has not been fully investigated among adolescents. In this study, we tested the association of kynurenine pathway metabolites with risk for and remission of adolescent depression and whether abnormalities in the kynurenine pathway are sex specific. METHODS: Kynurenine pathway metabolites were measured in plasma at baseline in the IDEA-RiSCo (Identifying Depression Early in Adolescence Risk-Stratified Cohort), a longitudinal study of adolescents (15.6 ± 0.8 years; 50% female) stratified into 3 groups (each n = 50): 1) at low risk for developing depression, 2) at high risk for developing depression, or 3) with MDD. Adolescents with MDD at baseline were followed up after 3 years (n = 41) to assess remission or persistence of MDD. RESULTS: Cross-sectional analyses at baseline showed that adolescents at high risk for depression and adolescents with MDD had lower kynurenic acid concentrations and kynurenic acid/quinolinic acid ratio than low-risk adolescents. These differences were not present in males but appeared to be driven by females. Proinflammatory cytokines positively correlated with neurotoxic metabolites, specifically in the high-risk and MDD groups. Female individuals with persistent MDD at the 3-year follow-up showed lower baseline kynurenine and higher 3-hydroxykynurenine/kynurenine ratio than those who experienced remission at 3-year follow-up. CONCLUSIONS: The findings suggest a sex-specific kynurenine pathway alteration in adolescent depression. Female adolescents at higher risk for or with depression showed a reduction in neuroprotective metabolites. An increased diversion of kynurenine toward production of neurotoxic metabolites predicted persistent depression in female adolescents with MDD.