As if adolescence is hard enough – with the onset of puberty, the emergence of peer pressure, and sudden (and often self imposed) assault on one’s self esteem – it’s a time when roughly three-quarters of mental health issues crop up. Yet figuring out why some problems – such as depression – hit young girls more often remains challenging.
A group of UK researchers have published a paper that touts the discovery of a biological pathway that could offer an explanation. The study details how an imbalance in neurotoxic and neuroprotective metabolites within the kynurenine pathway might contribute to the onset and persistence of teen major depressive disorder (MDD).
“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,” Senior author and King’s College London Clinical Professor of Psychoneuroimmunology Valeria Mondelli said. “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.”
Topline Results
The researchers sought to get a better understanding of the kynurenine pathway, which is responsible for metabolizing tryptophan. This pathway also produces both neuroprotective metabolites – such as kynurenic acid – and neurotoxic metabolites – such as quinolinic acid. Multiple studies have revealed that an imbalance between these products could be tied to adult depression. But this new data expands that understanding to adolescents.
The team studied a cohort of Brazilian adolescents that included those at low risk for depression, higher-risk individuals, and some who’d already been diagnosed. They found that:
- Adolescents at higher risk (or with MDD) displayed lower kynurenic acid levels and a reduced kynurenic acid/quinolinic acid ratio compared to their lower-risk peers.
- Differences between cohorts appeared to be most stark among the female participants. (They found no significant changes in the young men.)
- Inflammation markers – such as proinflammatory cytokines – dovetailed with higher neurotoxic metabolite levels in those at higher risk or already diagnosed with MDD.
Notably, the researchers discovered that female adolescents with persistent depression exhibited lower baseline kynurenine levels and a higher ratio of 3-hydroxykynurenine to kynurenine in a three-year follow-up. This, they suggested, hints at a greater tendency toward neurotoxic metabolite production.
“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,” first author and King’s College Senior Research Associate Naghmeh Nikkheslat, PhD, added. “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.”
Biological Mechanism Behind Depression
Enzymes like tryptophan 2,3-dioxygenase (TDO) and indoleamine-2,3-dioxygenase (IDO) ultimately shape the kynurenine pathway. This substrate then breaks off into one of two routes:
- The neuroprotective route produces kynurenic acid, which safeguards against neuron damage by blocking NMDA receptors, or;
- The neurotoxic route produces quinolinic acid, which over-stimulates the NMDA receptors, inducing oxidative stress and neuron damage.
Proinflammatory cytokines, normally elevated in MDD patients, amplify IDO and kynurenine 3-monooxygenase (KMO) enzyme activity, steering tryptophan metabolism toward the neurotoxic pathway. This dynamic is more pronounced in those at higher depression risk or already living with MDD.
Female-Specific Depression Vulnerability
This new data illustrates that biological sex drives – for the most part – these pathway imbalances. Female adolescents, already at a higher risk for developing depression during puberty, appear to be more susceptible to kynurenine pathway disruptions. Hormonal changes – specifically estrogen’s interaction with immune responses and tryptophan metabolism – could explain this.
Finally, it’s worth mentioning that while contraceptive use has been tied to lower kynurenic acid levels in some studies, the researchers couldn’t identify any such influence in this study. Less than a third of participants reported using hormonal contraceptives. Even so, the kynurenine alterations remained.
Treatment Implications
Ultimately, the results of this study could dramatically improve our ability to identify at-risk adolescents earlier and more effectively. By measuring kynurenine pathway metabolites, clinicians might be able to better predict and manage depressive symptoms, especially in female patients.
And future treatment strategies that target the kynurenine pathway specifically, could help stave off – or at least minimize – long-term depressive outcomes.
Additionally, the research underscores the potential value of anti-inflammatory therapies in depression management. Given the robust link between inflammation, kynurenine metabolism, and MDD, interventions that reduce inflammation might help restore the balance between neuroprotective and neurotoxic metabolites.
Further Reading
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