The kynurenine pathway may explain why teenage girls are more prone to depression, with inflammation linked to more harmful brain chemicals.
Depression is a mental health condition affecting approximately 280 million people worldwide. It is twice as common in women as in men, a disparity that begins to emerge during adolescence. While previous research has explored the biological mechanisms underlying depression in adults, highlighting the potential role of the kynurenine pathway, this is the first study to examine the pathway in adolescents, specifically in relation to biological sex.
Published in Biological Psychiatry, the study was funded by MQ Mental Health Research and supported by the National Institute for Health and Care Research (NIHR) Maudsley Biomedical Research Centre (BRC).
The kynurenine pathway is a metabolic process that breaks down tryptophan, an amino acid present in many foods. In the brain, this breakdown can follow two distinct routes: one that generates neuroprotective compounds, and another that leads to the production of neurotoxic substances. Key byproducts include kynurenic acid, which protects brain cells, and quinolinic acid, which can be harmful to them.
Adolescent Depression and Biological Differences
Senior author Professor Valeria Mondelli, Clinical Professor of Psychoneuroimmunology at King’s IoPPN and theme lead for Mood Disorders and Psychosis at NIHR Maudsley BRC said: “Adolescence is a time when many changes occur in the brain and body but we still know very little about the possible biological drivers for depression and how this might affect the difference between teenage boys and girls. Our study indicates the ‘kynurenine pathway’ plays a role in development of depression during the teenage years which may help us to understand why there is a higher incidence amongst girls. During adolescence, there are a wide range of social and individual factors that influence mental health, and by identifying the biological pathways involved we hope we can help build a clearer picture of how we can help teenagers manage depression.”
Using blood tests, the study assessed the levels of kynurenic and quinolinic acids in a group of 150 teenagers from Brazil aged between 14 and 16. The teenagers belonged to one of three groups – those with low risk of depression, those with high risk of depression, and those who had been diagnosed with depression. Risk was assessed using a measure that had been developed as part of the Identifying Depression Early in Adolescence (IDEA) project and considers a range of factors.
There were 50 adolescents in each group and they were evenly divided by biological sex to explore differences between male and female adolescents. The adolescents were tracked over three years to assess if their depression symptoms persisted or improved.
Neuroprotective and Neurotoxic Compounds
King’s College London researchers found that adolescents with a higher risk for depression or who have a current diagnosis of depression had lower levels of kynurenic acid, the neuroprotective compound. This reduction was most evident in female adolescents, suggesting that girls might be more vulnerable to the harmful effects of an imbalanced kynurenine pathway during adolescence, potentially explaining why females experience depression at higher rates.
The study also measured specific proteins in the blood that indicate the body is in an inflammatory state, and are released during infection, stress, or illness. It found that higher levels of these inflammatory markers were linked to increased production of neurotoxic chemicals in the kynurenine pathway. Notably, this association was found in adolescents at high-risk or with depression, but not in low-risk adolescents. This suggests that inflammation might drive the kynurenine pathway toward producing neurotoxic chemicals, increasing the risk of depression.
In the follow-up three years later, the study showed that female adolescents with persistent depression had higher levels of neurotoxic metabolites than those who recovered over time, suggesting that increased neurotoxic activity in the kynurenine pathway could make depression harder to overcome for some adolescents
First author and Senior Research Associate at King’s IoPPN Dr Naghmeh Nikkheslat said, “Our study indicates that the measurement of chemicals involved in the kynurenine pathway could potentially help identify those who at risk of persistent depression, particularly amongst females, as well as inform the approaches we take to providing support. This insight could help develop more targeted support for teenagers with depression through interventions that work in a range of ways on the kynurenine pathway from medication to lifestyle changes such as diet and exercise.”
Reference: “Sex-Specific Alterations of the Kynurenine Pathway in Association With Risk for and Remission of Depression in Adolescence” by 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 and Valeria Mondelli, 25 March 2025, Biological Psychiatry.
DOI: 10.1016/j.biopsych.2024.11.020
Funding: MQ: Transforming Mental Health, National Institute for Health Research
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