High copper and low folate levels implicated in depression risk

A study published in the journal Frontiers in Nutrition​ ​assessed data from the National Health and Nutrition Examination Survey (NHANES), investigating the effect of trace elements in 4,847 participants with varying responses to a questionnaire on mental health. 

Results showed that patients with both higher serum copper levels and folate deficiency were found to have the highest risk of depression.

“This emerging research exploring the link between nutrients and depressive symptoms offers a promising alternative or adjunctive approach to traditional treatments,” the authors from China noted. 

Commenting independently on the paper, clinical neuroscientist and applied microbiologist Dr. Miguel Toribio-Mateas told NutraIngredients that the findings "provide support to the fact that dietary factors should be considered in the broader context of mental health treatment," noting that the research aligned with "growing recognition in the field that treating conditions like depression may require a multi-faceted approach."

Increasing depression rates​

Depression significantly impairs daily functioning and quality of life​, and its prevalence has increased dramatically: According to research​, global cases rose from 172 million in 1990 to 258 million in 2017, an increase of 49.86%.

Nutritional factors like copper and folate have already been linked to depression, with research suggesting that high copper levels​ and folate deficiency​ may exacerbate depressive symptoms. 

However, the relationship between these nutrients and depression, particularly their combined effects, remains underexplored.

Low folate linked to depression​ 

NHANES data (2011 to 2016) from participants between the ages of 18 and 80 were analyzed to examine the role of trace elements.

The researchers included participants with information on copper and folate levels and a completed nine-item Patient Health Questionnaire (PHQ-9) which assessed depression. 

Among the 4,847 participants selected for this study, 429 had PHQ-9 scores above 10, which were defined as having depressive symptoms. Among those subjects, higher serum copper levels and folate deficiency were associated with an increased risk of depression. 

The findings confirmed that high copper levels and low folate levels were independent risk factors for depression, with a suggested synergistic effect when both conditions are present, contributing to 19% of depression cases.

“By identifying specific nutrients that may play a role in modulating mood and cognitive function, it may be possible to develop safer and more cost-effective strategies for reducing the residual risk of depression,” the researchers wrote. 

“If further research confirms that balancing certain nutrient levels can help alleviate depressive symptoms, this could lead to the development of personalized nutrition plans tailored to individual needs—such an approach could not only improve mental health outcomes but also reduce reliance on pharmacological treatments and their associated side effects.”

Mechanistic action 

As Toribio-Mateas explained, elevated copper levels and folate deficiency can disrupt brain function and contribute to depressive symptoms through distinct mechanisms. 

“High copper levels are associated with increased oxidative stress, which can damage neurons and interfere with the balance of neurotransmitters such as dopamine, noradrenaline and serotonin, all of which play essential roles in regulating mood,” he said. 

“Folate deficiency, on the other hand, is linked to reduced synthesis of neurotransmitters due to impaired methylation processes. It is essential for converting homocysteine to methionine, a precursor to neurotransmitters, and without sufficient folate, homocysteine levels rise, leading to neurotoxicity and potentially exacerbating depressive symptoms.”

The role of the gut microbiota​

Toribio-Mateas also highlighted the important role of gut microbiota in modulating the bioavailability and metabolism of both copper and folate.

“Some gut microbes are involved in the synthesis of folate, such as some strains of Lactiplantibacillus plantarum​ and Latilactobacillus sakei​, as well as Bifidobacterium adolescentis​, B. bifidum​, B. catenulatum​, and B. pseudocatenulatum​ can produce folate as part of their metabolic activities,” he said.

Disruptions to the composition of the gut microbiota, however, may exacerbate folate deficiency, which could further contribute to depression. Additionally, gut microbiota can influence copper absorption and its subsequent effects on the brain, therefore dysbiosis may lead to chronically increased intestinal permeability, a situation that would allow more copper to enter the bloodstream and potentially reach toxic levels in the brain.

As healthy gut microbial composition is essential for maintaining optimal levels of trace elements and protecting against depression, dietary interventions that support gut health could offer a promising approach to mitigating the risks of depression, Toribio-Mateas noted.

"Probiotic and prebiotic foods that promote a healthy microbiome may enhance folate production and improve copper metabolism, reducing their potential negative impacts on mental health, and a personalized approach that considers an individual’s gut microbiome composition could significantly enhance the effectiveness of folic acid supplementation in preventing or treating depression," he added.

"The potential synergistic effect between copper and folate in depression risk highlights the need for a more integrative approach that considers multiple aspects of a person’s biology, including nutrient levels, genetic predisposition and gut health."

Journal: Frontiers in Nutrition​
doi: 10.3389/fnut.2024.1389480​ 
"Independent and combined effect of serum copper and folate on depression: cross-sectional data from the NHANES 2011–2016"
Authors: Liu, M. Et al.