{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T02:44:55Z","timestamp":1790649895149,"version":"4.1.0"},"reference-count":34,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2024,8,9]],"date-time":"2024-08-09T00:00:00Z","timestamp":1723161600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Nutr."],"abstract":"<jats:sec><jats:title>Background and objective<\/jats:title><jats:p>Depression is a widespread mental health condition that can impact both mental and physical well-being. Prior research has shown that high levels of copper in the blood and low levels of folate are linked to depression. This study aimed to explore whether serum folate levels, independently or in combination with serum copper levels, associated with the risk of depression.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Data from participants aged 18\u201380\u2009years in the National Health and Nutrition Examination Survey (NHANES) from 2011 to 2016 were analyzed to examine the role of trace elements. Depression was assessed using the nine-item Patient Health Questionnaire (PHQ-9). Logistic regression analyses were employed to evaluate the main effect of serum copper and folate levels on depression. Three indices, including the relative excess risk of interaction (RERI), attributable proportion of interaction (API), and synergy index (SI), were used to analyze the interaction effect.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Among the 4,847 participants selected for this study, 429 (8.9%) had PHQ-9 scores above 10, which we defined as having depressive symptoms. After adjusting for all confounding factors, higher serum copper levels [\u226515.5 vs. &amp;lt;15.5\u2009\u03bcmol\/L, odds ratio (OR): 1.54; 95% confidence intervals (CI): 1.18\u20132.11] and folate deficiency (folate \u226553.7 vs. &amp;lt;53.7\u2009\u03bcmol\/L, OR: 1.44; 95% CI: 1.21\u20132.10) were associated with an increased risk of depression. Patients with both higher serum copper levels and folate deficiency (OR: 2.11; 95% CI: 1.43\u20133.14) had the highest risk of depression than other levels. High copper levels and low folate levels are associated with the occurrence of depression symptoms, and there may be a synergistic effect between them (SI: 1.65; 95% CI: 1.49\u20134.76), with this interaction accounting for 19% of depression cases (API: 0.19; 95% CI: 0.01\u20130.54).<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>There may be a synergistic interaction between high copper levels and low folate levels associated with increasing risk of depression. Further population-based interventional studies are needed to confirm whether folic acid supplementation is effective in preventing depression in individuals with high blood copper levels.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fnut.2024.1389480","type":"journal-article","created":{"date-parts":[[2024,8,9]],"date-time":"2024-08-09T04:42:30Z","timestamp":1723178550000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":2,"title":["Independent and combined effect of serum copper and folate on depression: cross-sectional data from the NHANES 2011\u20132016"],"prefix":"10.3389","volume":"11","author":[{"given":"Mengqing","family":"Liu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gang","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chongfei","family":"Jiang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2024,8,9]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"2214","DOI":"10.1001\/jama.2016.17324","article-title":"Prevalence of depression, depressive symptoms, and suicidal ideation among medical students: a systematic review and Meta-analysis","volume":"316","author":"Rotenstein","year":"2016","journal-title":"JAMA"},{"key":"ref2","doi-asserted-by":"publisher","first-page":"2433","DOI":"10.1001\/archinte.163.20.2433","article-title":"Depression and pain comorbidity: a literature review","volume":"163","author":"Bair","year":"2003","journal-title":"Arch Intern Med"},{"key":"ref3","doi-asserted-by":"publisher","first-page":"121","DOI":"10.1007\/s11920-022-01326-3","article-title":"Moderators of cognitive behavioral treatment for insomnia on depression and anxiety outcomes","volume":"24","author":"Mirchandaney","year":"2022","journal-title":"Curr Psychiatry Rep"},{"key":"ref4","doi-asserted-by":"publisher","first-page":"134","DOI":"10.1016\/j.jpsychires.2019.08.002","article-title":"Changes in the global burden of depression from 1990 to 2017: findings from the global burden of disease study","volume":"126","author":"Liu","year":"2020","journal-title":"J Psychiatr Res"},{"key":"ref5","doi-asserted-by":"publisher","first-page":"506","DOI":"10.1016\/j.psychres.2018.05.049","article-title":"Copper in depressive disorder: a systematic review and meta-analysis of observational studies","volume":"267","author":"Ni","year":"2018","journal-title":"Psychiatry Res"},{"key":"ref6","doi-asserted-by":"publisher","first-page":"175","DOI":"10.1177\/1099800413479156","article-title":"The plasma concentration of copper and prevalence of depression were positively correlated in shift nurses","volume":"16","author":"Chang","year":"2014","journal-title":"Biol Res Nurs"},{"key":"ref7","doi-asserted-by":"publisher","first-page":"68","DOI":"10.1016\/j.jad.2017.12.004","article-title":"Association of total zinc, iron, copper and selenium intakes with depression in the US adults","volume":"228","author":"Li","year":"2018","journal-title":"J Affect Disorders"},{"key":"ref8","doi-asserted-by":"publisher","first-page":"847","DOI":"10.3390\/nu11040847","article-title":"Low zinc, copper, and manganese intake is associated with depression and anxiety symptoms in the Japanese working population: findings from the eating habit and well-being study","volume":"11","author":"Nakamura","year":"2019","journal-title":"Nutrients"},{"key":"ref9","doi-asserted-by":"publisher","first-page":"1748","DOI":"10.1038\/s41430-022-01181-8","article-title":"Relationship of serum copper and zinc with kidney function and urinary albumin to creatinine ratio: cross-sectional data from the NHANES 2011-2016","volume":"76","author":"Jiang","year":"2022","journal-title":"Eur J Clin Nutr"},{"key":"ref10","doi-asserted-by":"publisher","first-page":"9","DOI":"10.1016\/j.jpsychires.2017.07.019","article-title":"The association of folate and depression: a meta-analysis","volume":"95","author":"Bender","year":"2017","journal-title":"J Psychiatr Res"},{"key":"ref11","doi-asserted-by":"publisher","first-page":"e13104","DOI":"10.1111\/dth.13104","article-title":"Depression, isotretinoin, and folic acid: a practical review","volume":"32","author":"Abdelmaksoud","year":"2019","journal-title":"Dermatol Ther"},{"key":"ref12","doi-asserted-by":"publisher","first-page":"727","DOI":"10.1017\/S1041610215000046","article-title":"Systematic review and meta-analysis of randomized placebo-controlled trials of folate and vitamin B12 for depression","volume":"27","author":"Almeida","year":"2015","journal-title":"Int Psychogeriatr"},{"key":"ref13","doi-asserted-by":"publisher","first-page":"59","DOI":"10.1177\/0269881105048899","article-title":"Treatment of depression: time to consider folic acid and vitamin B12","volume":"19","author":"Coppen","year":"2005","journal-title":"J Psychopharmacol"},{"key":"ref14","doi-asserted-by":"publisher","first-page":"2","DOI":"10.1192\/bja.2019.68","article-title":"Vitamin and mineral supplementation for maintaining cognitive function in cognitively healthy people in mid and late life: a Cochrane review","volume":"26","author":"Rutjes","year":"2020","journal-title":"BJPsych Adv"},{"key":"ref15","doi-asserted-by":"publisher","first-page":"332","DOI":"10.1024\/0300-9831.76.5.332","article-title":"Folate deprivation and copper exposure potentiate reactive oxygen species generation and chromosomal DNA loss but not mitochondrial DNA deletions in rat hepatocytes","volume":"76","author":"Lin","year":"2006","journal-title":"Int J Vitam Nutr Res"},{"key":"ref16","article-title":"National Health and nutrition examination survey 2011-2012 data documentation, codebook, and frequencies. Copper, Selenium & Zinc \u2014 serum (CUSEZN_G)","year":""},{"key":"ref17","article-title":"National Health and nutrition examination survey 2013-2014 data documentation, codebook, and frequencies copper, Selenium & Zinc \u2014 serum (CUSEZN_H)","year":""},{"key":"ref18","article-title":"National Health and nutrition examination survey 2015-2016 data documentation, codebook, and frequencies copper, Selenium & Zinc \u2014 serum (CUSEZN_I)","year":""},{"key":"ref19","year":""},{"key":"ref20","year":""},{"key":"ref21","doi-asserted-by":"publisher","first-page":"S454","DOI":"10.1002\/acr.20556","article-title":"Measures of depression and depressive symptoms: Beck depression inventory-II (BDI-II), Center for Epidemiologic Studies Depression Scale (CES-D), geriatric depression scale (GDS), hospital anxiety and depression scale (HADS), and patient health Questionnaire-9 (PHQ-9)","volume":"63","author":"Smarr","year":"2011","journal-title":"Arthritis Care Res"},{"key":"ref22","doi-asserted-by":"publisher","first-page":"606","DOI":"10.1046\/j.1525-1497.2001.016009606.x","article-title":"The PHQ-9: validity of a brief depression severity measure","volume":"16","author":"Kroenke","year":"2001","journal-title":"J Gen Intern Med"},{"key":"ref23","doi-asserted-by":"publisher","first-page":"604","DOI":"10.7326\/0003-4819-150-9-200905050-00006","article-title":"A new equation to estimate glomerular filtration rate","volume":"150","author":"Levey","year":"2009","journal-title":"Ann Intern Med"},{"key":"ref24","doi-asserted-by":"publisher","first-page":"351","DOI":"10.1016\/S0304-4165(99)00043-4","article-title":"Folate and homocysteine metabolism in copper-deficient rats","volume":"1427","author":"Tamura","year":"1999","journal-title":"Biochim Biophys Acta"},{"key":"ref25","doi-asserted-by":"publisher","first-page":"583","DOI":"10.1079\/PNS19940067","article-title":"Newer aspects of micronutrients in chronic disease: copper","volume":"53","author":"Strain","year":"1994","journal-title":"Proc Nutr Soc"},{"key":"ref26","doi-asserted-by":"publisher","first-page":"797S","DOI":"10.1093\/ajcn\/63.5.797","article-title":"Copper biochemistry and molecular biology","volume":"63","author":"Linder","year":"1996","journal-title":"Am J Clin Nutr"},{"key":"ref27","doi-asserted-by":"publisher","first-page":"1254","DOI":"10.1126\/science.abf0529","article-title":"Copper induces cell death by targeting lipoylated TCA cycle proteins","volume":"375","author":"Tsvetkov","year":"2022","journal-title":"Science"},{"key":"ref28","doi-asserted-by":"publisher","first-page":"35","DOI":"10.1016\/j.mrgentox.2016.02.002","article-title":"Genotoxicity and cytotoxicity of chromium, copper, manganese and lead, and their mixture in WIL2-NS human B lymphoblastoid cells is enhanced by folate depletion","author":"Alimba","year":"2016","journal-title":"Mutat Res Genet Toxicol Environ Mutagen"},{"key":"ref29","first-page":"677","article-title":"Review: chemical pathology of homocysteine VI. Aging, cellular senescence, and mitochondrial dysfunction","volume":"48","author":"KS","year":"2018","journal-title":"Ann Clin Lab Sci"},{"key":"ref30","doi-asserted-by":"publisher","first-page":"104193","DOI":"10.1016\/j.mvr.2021.104193","article-title":"Folic acid alleviates the blood brain barrier permeability and oxidative stress and prevents cognitive decline in sepsis-surviving rats","volume":"137","author":"Novochadlo","year":"2021","journal-title":"Microvasc Res"},{"key":"ref31","doi-asserted-by":"publisher","first-page":"927","DOI":"10.1016\/B978-0-7020-4087-0.00061-9","article-title":"The neurology of folic acid deficiency","volume":"120","author":"Reynolds","year":"2014","journal-title":"Handb Clin Neurol"},{"key":"ref32","doi-asserted-by":"publisher","first-page":"230","DOI":"10.1016\/j.neuro.2019.07.007","article-title":"The role of zinc, copper, manganese and iron in neurodegenerative diseases","volume":"74","author":"Mezzaroba","year":"2019","journal-title":"Neurotoxicology"},{"key":"ref33","doi-asserted-by":"publisher","first-page":"595","DOI":"10.1079\/PHN2001325","article-title":"A review of the MAFF optimal nutrition status research programme: folate, iron and copper","volume":"5","author":"Buttriss","year":"2002","journal-title":"Public Health Nutr"},{"key":"ref34","doi-asserted-by":"publisher","first-page":"473","DOI":"10.1016\/j.jad.2020.09.131","article-title":"Screening for depression in primary care with patient health Questionnaire-9 (PHQ-9): a systematic review","volume":"279","author":"Costantini","year":"2021","journal-title":"J Affect Disord"}],"container-title":["Frontiers in Nutrition"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fnut.2024.1389480\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,8,9]],"date-time":"2024-08-09T04:42:34Z","timestamp":1723178554000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fnut.2024.1389480\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,8,9]]},"references-count":34,"alternative-id":["10.3389\/fnut.2024.1389480"],"URL":"https:\/\/doi.org\/10.3389\/fnut.2024.1389480","relation":{},"ISSN":["2296-861X"],"issn-type":[{"value":"2296-861X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,8,9]]},"article-number":"1389480"}}