When the body experiences inflammation, an immune response that occurs during infection, stress, or illness, the kynurenine pathway is pushed towards 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 IDEA project uniquely aimed to investigate if a similar imbalance occurs in adolescents, and if there are notable differences between males and females.
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 the harmful effects of an imbalanced kynurenine pathway during adolescence, 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 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.
Moreover, 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 personalized 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 avenues for treating depression.