A key Biological Mechanism Linked to Depression Risk and Recovery in Teenage Girls

Trigger Warning: This post contains mention of suicide and mental health struggles, which may be distressing for some readers. Please take care of yourself and consider skipping this content if it may be triggering. If you need support, consider reaching out to a mental health professional or contacting a crisis support service in your area.

Understanding Depression in Adolescence

I am Dr Naghmeh Nikkheslat, a Senior Research Scientist at the Institute of Psychiatry, Psychology & Neuroscience at King’s College London. I am working on a study funded by the MQ Transforming Mental Health Charity. The study is called “Identifying Depression Early in Adolescence (IDEA)” co-led by Prof Valeria Mondelli and Dr Christian Kieling. In this piece, I am going to talk about my research into the understanding of depression in adolescence.

Depression is a mental health condition that affects millions, often beginning in adolescence or early adulthood. Going through puberty, adolescent girls are twice as likely as boys to develop clinical depression, which greatly affects our ability to feel happy and enjoy life. Adolescent depression is a serious concern as not only can it negatively impact social and functional development, but it can also increase the risk of suicide.

While scientists have studied depression in adults, they know much less about how biological processes drive depression in adolescents, particularly across sexes. This gap in understanding is crucial because identifying these underlying factors can guide and improve preventive approaches.

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 Study Design: Focusing on Brazilian adolescents

As part of the IDEA project, we studied 150 Brazilian adolescents aged 14 to 16. Since 90% of the world’s adolescents live in low and middle-income countries, we decided to focus specifically on adolescents living in one of these countries, such as Brazil. The 150 adolescents included in our study were divided into three groups:

1. Low-risk for depression

2. High-risk for depression

3. Adolescents diagnosed with depression.

They were evenly divided by biological sex to explore differences between male and female adolescents. The adolescents were also tracked over three years to see if their depression symptoms persisted or improved.

The Kynurenine Pathway and Its Role in Depression

As part of this study, I was particularly interested in investigating a biological mechanism, known as the “kynurenine pathway”. The kynurenine pathway comprises a series of chemical reactions that process tryptophan, an amino acid found in foods and the building block for serotonin, the “feel-good” neurotransmitter that regulates our mood. When tryptophan is broken down, it can either produce neuroprotective (brain-protecting) or neurotoxic (brain-damaging) chemicals. This process involves several byproducts like kynurenic acid (neuroprotective) and quinolinic acid (neurotoxic).

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When the body experiences inflammation, an immune response occurring during infection, stress, or illness, the kynurenine pathway is prone to producing more neurotoxic chemicals. Prolonged inflammation appears to activate factors that convert tryptophan into kynurenine and ultimately into neurotoxic byproducts. This shift can lead to brain tissue damage, decrease serotonin levels, and contribute to depressive symptoms.

In adults with depression, research has shown an imbalance in this pathway, with more neurotoxic than neuroprotective chemicals being produced. Therefore, our project aimed to investigate if a similar imbalance occurs in adolescents and if there are notable differences between males and females.

Key Findings: A Gendered Pathway to Depression

Measuring kynurenine pathway products, we found that adolescents with a higher risk for depression or a current diagnosis of depression had lower levels of kynurenic acid, the neuroprotective compound. This reduction was most evident in female adolescents, suggesting that females might be more vulnerable to this imbalanced kynurenine pathway, potentially explaining why females experience depression at higher rates, especially during adolescence, when hormonal changes may further intensify these effects.

In addition, our study looked at inflammatory markers, specific proteins that indicate the body is in an inflammatory state. We found that higher levels of 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, our 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 could make depression harder to overcome for some adolescents. Therefore, measuring kynurenine pathway chemicals in adolescence could potentially help identify those at risk of persistent depression, particularly in females.

Implications for Treatment and Prevention

The findings from this study suggest that targeting the kynurenine pathway could provide a more personalised treatment for female adolescents struggling with depression. Reducing inflammation or shifting the kynurenine pathway back toward producing neuroprotective rather than neurotoxic metabolites may help prevent the progression or chronic nature of depression, particularly in females. New treatment strategies or lifestyle changes, such as dietary interventions or therapies that restore the balance between neuroprotective and neurotoxic chemicals, could offer new directions for treating depression.

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A New Path to Prevention

By identifying the kynurenine pathway as one of the key mechanisms in adolescent depression, especially among females, this study points to the potential of developing sex-specific treatments that could intervene early and opens doors for personalised preventive approaches. For adolescents, early detection of biological markers could make a real difference, enabling interventions before symptoms become severe.

This research represents a hopeful step toward targeted interventions that recognise the unique biological factors shaping mental health in teenage years, especially for girls who are more vulnerable during this critical period of development.