December 16, 2025, 11:05 am | Read time: 6 minutes
Depression in youth is not just “a phase” but must be taken seriously as an illness. Girls are particularly often affected. A new study shows: An imbalance between certain substances in the brain could not only increase the risk of depression but also predict whether those affected will recover or not.
Worldwide, about 280 million people are affected by depression. Women are twice as likely to develop it as men.1 According to the Federal Statistical Office, cases in Germany are increasing, including among children and adolescents. In the age group of 15 to 24-year-olds, the number of cases has almost septupled.2 And here, too, it shows: Girls are more likely than boys to suffer from depression. But why is that? An international research team conducted a study with 150 adolescents to identify biological risk factors for depression in adolescence, particularly gender-specific differences in the so-called kynurenine metabolic pathway. This biochemical process can influence the balance between protection and damage in the brain. The researchers examined how this relates to the risk, course, and recovery from depression—and found significant differences between girls and boys.3
Overview
Researchers Examined a Specific Metabolic Process
The study examined the role of the kynurenine metabolism in connection with depression in adolescents, with a particular focus on gender-specific differences. This metabolic pathway is a central pathway for processing tryptophan, an amino acid that also serves to produce serotonin, our “happiness hormone.” The kynurenine pathway produces both protective (neuroprotective) and harmful (neurotoxic) substances for the brain. An imbalance of these metabolic products has already been found in adults with depression.4 But whether this imbalance also prevails in adolescence was previously unclear. The researchers wanted to clarify whether changes in this metabolic process occur in adolescents with an increased risk of depression or existing depression and whether these differ between girls and boys. Additionally, they investigated whether such changes could also predict the further course of depression.
150 Adolescents With and Without Depression Participated
The study was conducted under the leadership of scientists from King’s College London and the Universidade Federal do Rio Grande do Sul in Brazil. The data came from the IDEA-RiSCo cohort, a Brazilian long-term study with 150 adolescents aged 14 to 16 (English: Identifying Depression Early in Adolescence Risk Stratified Cohort). Participants were divided into three different groups and separated by gender:
- Group 1: low risk for depression
- Group 2: high risk
- Group 3: existing depression
The classification was based on a validated risk score for depression. All participants underwent comprehensive clinical examinations at the start, and blood samples were taken. Three years later, the adolescents with depression were re-examined to analyze the course of the disease. To measure kynurenine metabolites (the metabolic products), the team used a highly precise method called UHPLC-MS, short for ultra-high-performance liquid chromatography-tandem mass spectrometry. Additionally, inflammatory markers in the blood, known as cytokines, were analyzed. Cytokine levels are elevated, for example, during infections, stress, or illnesses. The data analysis was conducted using strict statistical procedures, including corrections for multiple tests, to ensure the validity of the results.
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Metabolism of Girls Produced a Type of “Neurotoxin”
The study showed that adolescents with a high risk of depression and those with depression had lower concentrations of the neuroprotective metabolite kynurenic acid than adolescents with low risk. The ratio of kynurenic acid to quinolinic acid—a neurotoxic metabolic product—was also significantly reduced in these groups. This “neurotoxin” increases oxidative stress in cells, leading to further damage. Elevated quinolinic acid levels are associated with many neuropsychiatric and neurodegenerative diseases, including anxiety disorders, depression, Alzheimer’s, Parkinson’s, and multiple sclerosis.5 Furthermore, in adolescents with high risk or existing depression, a positive correlation between pro-inflammatory cytokines and neurotoxic metabolites like quinolinic acid was observed—an indication of inflammation-enhanced damage processes in the brain.
Study Identified Gender-Specific Differences
Notably, these metabolic differences occurred only in female adolescents. Moreover, the researchers found further metabolic differences during the follow-up three years later. Girls with persistent depression had higher concentrations of neurotoxic metabolites than those who recovered over time. This suggests that increased neurotoxic activity in the kynurenine metabolic pathway could hinder overcoming depression in some adolescents.
What Is the Significance of the Results?
The results underscore that depression in adolescent girls is associated with biologically measurable changes in brain metabolism—particularly with a shift in balance toward neurotoxic substances. This metabolic change was not only associated with the onset of depression but also with its chronic course. Thus, the study identifies potential biomarkers that could help identify at-risk girls early and treat them specifically. The connection between inflammatory processes and neurotoxic metabolic products suggests that immune responses could play a central role in the development and chronicity of depression.
Lead author Dr. Naghmeh Nikkheslat hopes for better prevention options, as she explains in a press release: “These findings could help develop more targeted support for adolescents with depression through interventions that affect the kynurenine metabolism in various ways, from medications to lifestyle changes such as diet and exercise.”
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Classification of the Study and Possible Limitations
The study is the first of its kind to examine gender-specific changes in the kynurenine metabolism in adolescents. Its strengths lie in the carefully defined study design with clear risk stratification, the use of valid measurement methods, and the observation over three years. However, there are limitations: The metabolic products were only measured in the blood, although central processes occur in the brain—a direct statement about the brain can only be derived to a limited extent. Despite these limitations, the study provides important insights into gender-specific disease mechanisms.
Conclusion
The study shows for the first time that in girls with depression in adolescence, the kynurenine metabolism is disrupted—with a shift toward neurotoxic substances. These changes could not only indicate the risk of depression but also influence its course. The results suggest that biological markers like kynurenic acid and its ratios to other metabolites could be used for early detection and individualization of therapies. The research findings pave the way for gender-specific treatment approaches in the field of adolescent psychiatry.