Why Does Depression Affect Girls More? New Study May Hold the Answer

The study examined the relationship between depression in adolescence and a chemical imbalance in the brain, particularly in the kynurenine pathway, which can produce substances that are protective or toxic to neurons. The results showed that girls at higher risk or already diagnosed with depression had fewer neuroprotective substances and more neurotoxic substances, which can hinder recovery. In addition, inflammation appears to influence this imbalance. These findings help to better understand the biology of depression in adolescents and may contribute to new treatments.

Depression is a disorder that can begin as early as adolescence, a sensitive period of development. It is more common in females than in males, especially after puberty.

In addition to the emotional impacts, depression at this stage can impair school performance, social relationships and even increase the risk of suicide.

Despite improvements in our understanding of the biological mechanisms that underlie the development, pathogenesis and recurrence of adult depression, very little research has been conducted on the biological mechanisms involved in the risk and development of depression in adolescent populations, and in particular, focusing on potential differences between male and female adolescents.

This is crucial to inform the focus and targeting of preventive interventions. Furthermore, given that 90% of the world’s adolescents live in low- and middle-income countries, it is important to examine the biological mechanisms that underpin the development of depression in adolescents living in these contexts.

Scientists know that chemicals in the brain influence depression. One such chemical is tryptophan, an essential amino acid that can be converted to serotonin (a neurotransmitter associated with well-being) or follow another pathway, called the kynurenine pathway.

This pathway can lead to the production of substances that protect neurons (neuroprotective) or others that can be toxic to them (neurotoxic).

Research shows that in adults with depression, there is an imbalance in this pathway: there is more production of neurotoxic substances and less of neuroprotective ones.

In addition, inflammation in the body, which involves molecules called pro-inflammatory cytokines, can interfere with this pathway and lead to a higher risk of depression. The study wanted to understand whether this same imbalance occurs in adolescents and whether it affects boys and girls differently.

The current project was conducted as part of the IDEA-RiSCo (Identifying Depression Early in Adolescence Risk-Stratified Cohort) study, a longitudinal cohort recruited to investigate in-depth neurobiological, psychological, and environmental factors associated with increased risk and presence of depression.

After screening 7,720 adolescents from public schools in Porto Alegre, in southern Brazil, 150 adolescents aged 14 to 16 were selected for inclusion in the study. The researchers analyzed the levels of substances in the kynurenine pathway in the blood of Brazilian adolescents, divided into three groups:

1. Low risk of developing depression.

   
   

2. High risk of developing depression.

   
   

3. Already diagnosed with major depressive disorder (MDD).

They also followed the adolescents in the third group for three years to see if their depression persisted or improved. The results showed that adolescents in the second and third groups had fewer neuroprotective substances in their blood than those at low risk.

This effect appeared to be stronger in girls than in boys. Inflammatory substances were linked to an increase in neurotoxic substances, especially in the high-risk and already diagnosed groups.

Among the girls with depression, those who remained depressed three years later had a different chemical pattern in their blood from the beginning: less kynurenine and more neurotoxic substances.

The findings suggest that adolescent girls may be more vulnerable to depression due to biological differences in how their bodies process tryptophan. If this pathway is out of whack, it can increase the risk of depression and make recovery more difficult.

In addition, inflammation may play a role, helping to “push” the body to produce more toxic substances for the brain. These findings help us better understand the biological processes that contribute to depression in adolescents, which could lead to new, more effective and personalized treatments.

If scientists can balance this biochemical pathway, it may be possible to reduce the risk of depression or help people recover more quickly. In short, the research suggests that depression in adolescence, especially in girls, may be linked to a chemical imbalance in the brain that increases the production of neurotoxic substances, and this may be influenced by inflammation in the body.

This knowledge could be key to developing new prevention and treatment strategies in the future.

READ MORE:

Sex-Specific Alterations of the Kynurenine Pathway in Association With Risk for and Remission of Depression in Adolescence

Naghmeh Nikkheslat, Zuzanna Zajkowska, Cristina Legido-Quigley, Jin Xu, Pedro H. Manfro, Laila Souza, Rivka Pereira, Fernanda Rohrsetzer, Jader Piccin, Anna Viduani, Brandon A. Kohrt, Helen L. Fisher, Christian Kieling and Valeria Mondelli

Biological Psychiatry. 25 March 2025, 

DOI: 10.1016/j.biopsych.2024.11.020

Abstract: 

The imbalance between neurotoxic and neuroprotective metabolites of the kynurenine pathway has been implicated in the pathophysiology of major depressive disorder (MDD) in adulthood but has not been fully investigated among adolescents. In this study, we tested the association of kynurenine pathway metabolites with risk for and remission of adolescent depression and whether abnormalities in the kynurenine pathway are sex specific. Kynurenine pathway metabolites were measured in plasma at baseline in the IDEA-RiSCo (Identifying Depression Early in Adolescence Risk-Stratified Cohort), a longitudinal study of adolescents (15.6 ± 0.8 years; 50% female) stratified into 3 groups (each n = 50): 1) at low risk for developing depression, 2) at high risk for developing depression, or 3) with MDD. Adolescents with MDD at baseline were followed up after 3 years (n = 41) to assess remission or persistence of MDD. Cross-sectional analyses at baseline showed that adolescents at high risk for depression and adolescents with MDD had lower kynurenic acid concentrations and kynurenic acid/quinolinic acid ratio than low-risk adolescents. These differences were not present in males but appeared to be driven by females. Proinflammatory cytokines positively correlated with neurotoxic metabolites, specifically in the high-risk and MDD groups. Female individuals with persistent MDD at the 3-year follow-up showed lower baseline kynurenine and higher 3-hydroxykynurenine/kynurenine ratio than those who experienced remission at 3-year follow-up. The findings suggest a sex-specific kynurenine pathway alteration in adolescent depression. Female adolescents at higher risk for or with depression showed a reduction in neuroprotective metabolites. An increased diversion of kynurenine toward production of neurotoxic metabolites predicted persistent depression in female adolescents with MDD.