Biological pathway in brain could help explain why teenage girls more depressed than boys, finds study

Depression is a mental health condition that affects 280 million people worldwide. It is twice as common in women than men and this pattern starts to develop during adolescence. Researchers have studied the biological processes that drive depression in adults and shown a potential role for the kynurenine pathway, but this is the first time it has been investigated in adolescents in relation to biological sex.

The study was published in Biological Psychiatry and 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 series of chemical reactions that processes tryptophan, an amino acid found in foods. When tryptophan is broken down, it can take two routes in the brain: one that produces neuroprotective (brain-protecting) chemicals and another that produces neurotoxic (brain-damaging) chemicals. This process involves several byproducts including kynurenic acid (neuroprotective) and quinolinic acid (neurotoxic).

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 factors1. 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.

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 Alternations of Kyneurenine Pathway in Association with Risk and Remission of Depression in Adolescence. Nikkheslat, N. et al. Biological Psychiatry https://doi.org/10.1016/j.biopsych.2024.11.020.