Sex-Specific Alterations of the Kynurenine Pathway in Association With Risk for and Remission of Depression in Adolescence

Naghmeh Nikkheslat, Department of Psychological Medicine, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom; National Institute for Health and Care Research Maudsley Biomedical Research Centre at South London and Maudsley National Health Service Foundation Trust and King's College London, London, United Kingdom. Electronic address: naghmeh.nikkheslat@kcl.ac.uk.
Zuzanna Zajkowska, Department of Psychological Medicine, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom.
Cristina Legido-Quigley, Institute of Pharmaceutical Sciences, King's College London, London, United Kingdom.
Jin Xu, Institute of Pharmaceutical Sciences, King's College London, London, United Kingdom.
Pedro H. Manfro, Department of Psychiatry, School of Medicine, Universidade Federal do Rio Grande do Sul, Child and Adolescent Psychiatry Division, Hospital de Clínicas de Porto Alegre, Port Alegre, Brazil.
Laila Souza, Department of Psychiatry, School of Medicine, Universidade Federal do Rio Grande do Sul, Child and Adolescent Psychiatry Division, Hospital de Clínicas de Porto Alegre, Port Alegre, Brazil.
Rivka Pereira, Department of Psychiatry, School of Medicine, Universidade Federal do Rio Grande do Sul, Child and Adolescent Psychiatry Division, Hospital de Clínicas de Porto Alegre, Port Alegre, Brazil.
Fernanda Rohrsetzer, Department of Psychiatry, School of Medicine, Universidade Federal do Rio Grande do Sul, Child and Adolescent Psychiatry Division, Hospital de Clínicas de Porto Alegre, Port Alegre, Brazil.
Jader Piccin, Department of Psychiatry, School of Medicine, Universidade Federal do Rio Grande do Sul, Child and Adolescent Psychiatry Division, Hospital de Clínicas de Porto Alegre, Port Alegre, Brazil.
Anna Viduani, Department of Psychiatry, School of Medicine, Universidade Federal do Rio Grande do Sul, Child and Adolescent Psychiatry Division, Hospital de Clínicas de Porto Alegre, Port Alegre, Brazil.
Brandon A. Kohrt, Division of Global Mental Health, Department of Psychiatry, School of Medicine and Health Sciences, The George Washington University, Washington DC.
Helen L. Fisher, Social, Genetic & Developmental Psychiatry Centre, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom; Economic and Social Research Council Centre for Society and Mental Health, King's College London, London, United Kingdom.
Christian Kieling, Department of Psychiatry, School of Medicine, Universidade Federal do Rio Grande do Sul, Child and Adolescent Psychiatry Division, Hospital de Clínicas de Porto Alegre, Port Alegre, Brazil.
Valeria Mondelli, Department of Psychological Medicine, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom; National Institute for Health and Care Research Maudsley Biomedical Research Centre at South London and Maudsley National Health Service Foundation Trust and King's College London, London, United Kingdom.

Document Type

Journal Article

Publication Date

10-1-2025

Journal

Biological psychiatry

Volume

98

Issue

7

DOI

10.1016/j.biopsych.2024.11.020

Keywords

Adolescent depression; Inflammation; Kynurenic acid; Kynurenine pathway; Major depressive disorder; Neurotoxicity

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.

Department

Global Health

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