Why Depression Hits Girls Harder Than Boys

March 25, 2025 – Girls are twice as likely as boys to be diagnosed with depression, and researchers in London have now uncovered clues as to why.

Girls’ brains are more likely to use a common dietary amino acid called tryptophan in a way that is neurotoxic, or harmful to nerves, even though most people’s brains use it to make a compound that is neuroprotective, or helpful to nerves. Girls whose brains tended toward this neurotoxic process also were more likely to have blood test results that showed their bodies were in an inflammatory state.

The girls most likely to have these processes also scored highly on a depression risk assessment or had already been diagnosed with major depression. 

“Depression during adolescence can significantly impact social and emotional development and increases the risk of suicide,” said first author Naghmeh Nikkheslat, PhD, a senior research associate at King’s College London. “Our findings offer a hopeful step toward personalized, proactive approaches that address the underlying biological factors of depression, particularly in girls.”

The findings build on previous evidence showing that girls are more at risk of getting depression, highlighting the need for targeted prevention and treatment. An estimated 53% of teen girls reported persistent feelings of sadness or hopelessness, compared to 28% of boys, according to a 2024 CDC report. Girls were also more likely to have suicidal thoughts and behaviors.

The new study, which included 75 girls and 75 boys all around the age of 15 who lived in Brazil, showed that girls with depression, or at high risk of it, were more likely to have lower neuroprotective compound levels, compared to girls at low risk of depression. The differences were not seen among boys. The route these compounds take in the brain – either neuroprotective or neurotoxic – is called the kynurenine pathway.

“Our study suggests that targeting the kynurenine pathway may offer a personalized treatment avenue for female adolescents with depression,” said Nikkheslat. “By reducing inflammation or encouraging the pathway to produce more neuroprotective rather than neurotoxic metabolites, we may prevent depression from developing or becoming chronic.”

The researchers also found that high neurotoxic compound levels three years later were linked to an increased likelihood of persistent depression, while those whose levels had fallen were more likely to have recovered. This suggests that the neurotoxic activity makes depression harder to overcome, said Nikkheslat, who is an expert in the field of psychoneuroimmunology (the study of how the mind affects health and risk of disease).

Researchers are still working to understand why these chemical differences exist between boys and girls. But “we know that increased inflammation can potentially affect the levels of these chemicals,” Nikkheslat said. Childhood trauma or sexual hormones can impact inflammation, so it’s possible one or the other (or both) “could contribute to these chemical abnormalities in girls.”

Potential treatments to be evaluated may include anti-inflammatory medications to see if their use helps push the brain away from using the neurotoxic pathway, Nikkheslat said. Stress management, exercise, and dietary interventions known to reduce inflammation should also be considered. 

Tryptophan – the amino acid at the center of this research – is in many common foods like poultry, dairy, seeds, and nuts, and the body uses it for many essential processes like supporting infant growth, and in making melatonin and serotonin, the latter of which is important in regulating appetite and mood. Dietary approaches and the use of or development of medications that can impact how the brain ultimately uses the byproducts of tryptophan warrant exploration as possible treatments, Nikkheslat said, noting that it also could be lifesaving to identify girls at highest risk before they develop depression. 

SOURCES:

Naghmeh Nikkheslat, PhD, senior research associate, Institute of Psychiatry, Psychology & Neuroscience, King’s College London, United Kingdom.

Biological Psychiatry: “Sex-Specific Alterations of the Kynurenine Pathway in Association With Risk for and Remission of Depression in Adolescence.”