Kynurenine pathway may explain higher depression odds in adolescent girls

Kynurenine pathway may explain higher depression odds in adolescent girls | Image Credit: © primipil - © primipil - stock.adobe.com.

The kynurenine pathway and its role in depression

The kynurenine pathway may influence the disparity in depression rates based on biological sex among adolescents, according to a recent study published in Biological Psychiatry.¹

When tryptophan is broken down in the kynurenine pathway, it may take a route to produce brain-protecting chemicals or a route to produce brain-damaging chemicals, referred to as neuroprotective and neurotoxic chemicals, respectively. Multiple byproducts are involved in this process, including kynurenic acid and quinolinic acid.

“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,” said Valeria Mondelli, PhD, professor at King’s College London.

Study design and participant groups

The study was conducted to determine the role of the kynurenine pathway in the presence of depression.² Participants included adolescents aged 14 to 16 years stratified into groups based on depression risk. These groups included low risk, high risk, and a current major depressive disorder (MDD) diagnosis.

The Identifying Depression Early in Adolescence Risk Score was used to determine the risk of depression in patients. After the clinical assessment at baseline, follow-up occurred for approximately 3 years.

In the current analysis, only patients with MDD at baseline were evaluated. Remission was defined as MDD at baseline but not follow-up, and persistent depression as MDD at both baseline and the follow-up.

Measurement methods

Plasma tryptophan and downstream metabolites of the kynurenine pathway were quantified using the targeted ultrahigh-performance liquid chromatography tandem mass spectrometry with electrospray ionization method. Metabolites included kynurenic acid, anthranilic acid, kynurenine, quinolinic acid, picolinic acid, 3-hydroxykynurenine, and 3-hydroxyanthranilic acid.

The serum concentrations of proinflammatory cytokines were measured using the Meso Scale Discovery Multi-Plex Immunoassay technique. SPSS software version 29.0.2.0 (IBM Corp.) was used for statistical analysis.

Participant characteristics and kynurenine pathway metabolites

Participants were aged a mean 15 years, with a slightly reduced age on average in the low-risk group vs the high-risk and MDD groups. The lowest Mood and Feelings Questionnaire-Child scores were reported in the low-risk group and the highest in the MDD group. No significant differences were reported between male and female patients.

Significant differences in kynurenine pathway metabolites were reported between risk groups, with the high-risk group having significantly reduced kynurenic acid vs the low-risk group. Additionally, female adolescents in the high-risk and MDD groups reported lower kynurenine acid vs the low-risk group, but this difference was not reported in male patients.

The 3 groups also presented with significantly different kynurenic acid to quinolinic acid ratios, which indicate neuroprotection over neurotoxicity.Adolescents with increased depression risk and MDD reported lower ratios vs those as low risk. Notably, this ratio was reduced in female patients across groups, but not male patients.

Other metabolite findings and implications

Other kynurenine pathway metabolites and ratios did not differ between groups except for 3-hydroxyanthranilic acid. Additionally, no other metabolites presented differently between male and female patients.

Forty-one adolescents were included in the follow-up, 21 of whom went into remission while 20 had persistent MDD. Lower baseline kynurenine and a higher 3-hydroxykynurenine to kynurenine ratio was reported among female patients with persistent MDD vs their male counterparts.

These results indicated a change in the kynurenine pathway linked to depression in female patients, but not male patients. This includes a decline in neuroprotective metabolites and a disrupted balance between neuroprotection and neurotoxicity.

“Kynurenine pathway metabolites may help to develop preventive and personalized treatment strategies for MDD in female adolescents,” concluded investigators.

References

1. Biological pathway in the brain could help explain why teenage girls are more depressed than boys. King’s College London. March 25, 2025. Accessed March 26, 2025. https://www.eurekalert.org/news-releases/1077775
2. Nikkheslat N, Zajkowska Z, Legido-Quigley C, et al. Sex-specific alterations of the kynurenine pathway in association with risk for and remission of depression in adolescence. Biological Psychiatry. 2025. doi:10.1016/j.biopsych.2024.11.020