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Depression is a significant mental health challenge impacting approximately 280 million people globally. The condition is notably more prevalent among women, with the disparity beginning in the adolescent years. While previous research has explored the underlying biological mechanisms that contribute to depression in adults, this study marks the first examination of these processes in adolescents, focusing on the influence of biological sex.
The findings are detailed in a recent publication in Biological Psychiatry, with support from MQ Mental Health Research and the National Institute for Health and Care Research (NIHR) Maudsley Biomedical Research Centre (BRC).
Central to this research is the ‘kynurenine pathway,’ which encompasses a series of biochemical reactions that metabolize tryptophan, an essential amino acid obtained through diet. This metabolic process branches into two pathways in the brain: one yielding neuroprotective substances and another producing neurotoxic agents. Key byproducts of this pathway include kynurenic acid, a neuroprotective compound, and quinolinic acid, which is neurotoxic.
Professor Valeria Mondelli, the senior author and Clinical Professor of Psychoneuroimmunology at King’s IoPPN, highlighted the significance of adolescence as a period of substantial change within the brain and body, noting the scant understanding of the biological factors that contribute to depression and their differential impact on boys and girls. She stated, “Our study suggests that the kynurenine pathway plays a role in the development of depression during adolescence, shedding light on why incidence rates are higher among females. With various social and individual influences on mental health, identifying the biological pathways involved may guide us in supporting teenagers facing depression.”
The study involved blood tests conducted on 150 adolescents in Brazil, aged 14 to 16, categorized into three groups based on their depression risk: low risk, high risk, and those diagnosed with depression. Each group contained 50 participants, evenly split by biological sex to examine gender differences. Participants were followed for three years to observe the persistence or improvement of depressive symptoms.
Researchers at King’s College London discovered that teenagers identified as having a higher risk for or a current diagnosis of depression exhibited reduced levels of kynurenic acid, indicating a potential deficit in neuroprotection. This decrease was particularly pronounced among female adolescents, suggesting a heightened vulnerability among girls to the detrimental effects of an imbalanced kynurenine pathway, which may clarify the higher rates of depression experienced by females.
In addition, the study measured inflammatory markers in the participants’ blood, which are indicative of bodily responses to stress, infection, or illness. It was found that elevated levels of these markers were linked to the increased production of neurotoxic substances within the kynurenine pathway. Critically, this connection was significant only in the high-risk and diagnosed groups, implying that inflammation may push the kynurenine pathway towards generating neurotoxic compounds, thereby raising the risk for depression.
Follow-up evaluations after three years revealed that female adolescents with ongoing depression exhibited higher levels of neurotoxic metabolites compared to those who managed to recover, suggesting that heightened neurotoxic activity within the kynurenine pathway could complicate recovery from depression for certain individuals.
Dr. Naghmeh Nikkheslat, the first author and Senior Research Associate at King’s IoPPN, remarked, “Our findings indicate that assessing the chemicals involved in the kynurenine pathway may help identify adolescents at risk for persistent depression, particularly among females. This understanding could also inform tailored interventions aimed at providing support through various means, including medications and lifestyle modifications such as diet and physical activity.”
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