{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,10]],"date-time":"2026-11-10T18:54:12Z","timestamp":1794336852171,"version":"4.9.0"},"reference-count":90,"publisher":"MDPI AG","issue":"21","license":[{"start":{"date-parts":[[2025,10,24]],"date-time":"2025-10-24T00:00:00Z","timestamp":1761264000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Major depressive disorder (MDD) is a severe mental disorder associated with significant functional impairment and decreased quality of life. Growing evidence suggests that immune-inflammatory mechanisms, particularly cytokine dysregulation, take part in its development and course. This systematic review and meta-analysis aimed to evaluate whether cytokine alterations are present in early stages of MDD, specifically in first-episode (FE) and drug-na\u00efve (DN) patients. Following PRISMA guidelines a comprehensive search of PubMed, Scopus, and Web of Science was conducted in March 2025. Studies were eligible if they compared levels of inflammatory cytokines between adult FE or DN MDD patients and healthy controls (HCs). Meta-analyses using random-effects models were performed, including subanalyses depending on the source of the sample and the quality of the studies. In total, 17 eligible studies involving 1371 MDD patients were included. The meta-analysis showed significantly elevated levels of interleukin 6 (IL-6), interleukin 2 (IL-2), and tumor necrosis factor alfa (TNF-\u03b1) in FE patients compared to HCs. DN patients\u2019 quantitative analysis showed increased levels of IL-6, IL-2, interleukin 4 (IL-4), interleukin 10 (IL-10), TNF-\u03b1, and interferon gamma (IFN-\u03b3) compared to healthy individuals. Moreover, in the case of TNF-\u03b1, IL-2, interleukin 1 beta (IL-1\u03b2), and IL-4, there was a difference in results depending on the sample source (plasma\/serum). Cytokine dysregulation is present in first-episode and drug-na\u00efve MDD individuals. These findings highlight that the immune\u2013inflammatory response exists in the early stages of this disorder. Moreover, since more cytokines were elevated in DN patients, pharmacological antidepressant treatment might be a significant factor involved in inflammatory regulation in MDD. Nonetheless, future prospective studies with standardized protocols and division by clinical subtypes are needed to better understand the dynamics and clinical relevance of cytokine alterations in depression.<\/jats:p>","DOI":"10.3390\/ijms262110362","type":"journal-article","created":{"date-parts":[[2025,10,27]],"date-time":"2025-10-27T00:51:42Z","timestamp":1761526302000},"page":"10362","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":21,"title":["Altered Cytokine Levels in the First Episode of Major Depression and in Antidepressant-Na\u00efve Patients: A Systematic Review and Meta-Analysis"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9312-2976","authenticated-orcid":false,"given":"Adam","family":"G\u0119dek","sequence":"first","affiliation":[{"name":"Third Department of Psychiatry, Institute of Psychiatry and Neurology, 02-957 Warsaw, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-7688-9432","authenticated-orcid":false,"given":"Szymon","family":"Modrzejewski","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, Medical University of Lublin, 20-059 Lublin, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2224-3711","authenticated-orcid":false,"given":"Micha\u0142","family":"Materna","sequence":"additional","affiliation":[{"name":"Babinski Clinical Hospital, 30-393 Krakow, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-8933-0853","authenticated-orcid":false,"given":"Marcin","family":"Iwa\u0144ski","sequence":"additional","affiliation":[{"name":"Third Department of Psychiatry, Institute of Psychiatry and Neurology, 02-957 Warsaw, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5352-601X","authenticated-orcid":false,"given":"Adam","family":"Wichniak","sequence":"additional","affiliation":[{"name":"Third Department of Psychiatry, Institute of Psychiatry and Neurology, 02-957 Warsaw, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1423-2289","authenticated-orcid":false,"given":"Monika","family":"Dominiak","sequence":"additional","affiliation":[{"name":"Institute of Psychiatry and Neurology, 02-957 Warsaw, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,10,24]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2299","DOI":"10.1016\/S0140-6736(18)31948-2","article-title":"Depression","volume":"392","author":"Malhi","year":"2018","journal-title":"Lancet"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1146\/annurev-publhealth-031912-114409","article-title":"The Epidemiology of Depression Across Cultures","volume":"34","author":"Kessler","year":"2013","journal-title":"Annu. Rev. Public Health"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1045","DOI":"10.1016\/S0140-6736(11)60602-8","article-title":"Major Depressive Disorder: New Clinical, Neurobiological, and Treatment Perspectives","volume":"379","author":"Kupfer","year":"2012","journal-title":"Lancet"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"3","DOI":"10.2147\/NDT.S19617","article-title":"The increasing burden of depression","volume":"7","author":"Briley","year":"2011","journal-title":"Neuropsychiatr Dis Treat."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"234","DOI":"10.1016\/j.neuron.2020.06.002","article-title":"The Bidirectional Relationship of Depression and Inflammation: Double Trouble","volume":"107","author":"Beurel","year":"2020","journal-title":"Neuron"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1016\/j.biopsych.2022.11.003","article-title":"Inflammation-Related Functional and Structural Dysconnectivity as a Pathway to Psychopathology","volume":"93","author":"Goldsmith","year":"2023","journal-title":"Biol. Psychiatry"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1958","DOI":"10.1017\/S0033291719001454","article-title":"Prevalence of Low-Grade Inflammation in Depression: A Systematic Review and Meta-Analysis of CRP Levels","volume":"49","author":"Osimo","year":"2019","journal-title":"Psychol. Med."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"446","DOI":"10.1016\/j.biopsych.2009.09.033","article-title":"A Meta-Analysis of Cytokines in Major Depression","volume":"67","author":"Dowlati","year":"2010","journal-title":"Biol. Psychiatry"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"901","DOI":"10.1016\/j.bbi.2020.02.010","article-title":"Inflammatory Markers in Depression: A Meta-Analysis of Mean Differences and Variability in 5166 Patients and 5083 Controls","volume":"87","author":"Osimo","year":"2020","journal-title":"Brain Behav. Immun."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1093\/schbul\/sbx035","article-title":"Meta-Analysis of Cerebrospinal Fluid Cytokine and Tryptophan Catabolite Alterations in Psychiatric Patients: Comparisons Between Schizophrenia, Bipolar Disorder, and Depression","volume":"44","author":"Wang","year":"2018","journal-title":"Schizophr. Bull."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1016\/j.bbi.2020.11.024","article-title":"Structural Brain Correlates of Serum and Epigenetic Markers of Inflammation in Major Depressive Disorder","volume":"92","author":"Green","year":"2021","journal-title":"Brain Behav. Immun."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"104","DOI":"10.1016\/j.bbi.2015.01.003","article-title":"Effects of Chronic Interpersonal Stress Exposure on Depressive Symptoms Are Moderated by Genetic Variation at IL6 and IL1\u03b2 in Youth","volume":"46","author":"Tartter","year":"2015","journal-title":"Brain Behav. Immun."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1803","DOI":"10.1016\/j.psyneuen.2013.03.007","article-title":"Serotonin and Interleukin-6: The Role of Genetic Polymorphisms in IFN-Induced Neuropsychiatric Symptoms","volume":"38","author":"Udina","year":"2013","journal-title":"Psychoneuroendocrinology"},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Hassamal, S. (2023). Chronic Stress, Neuroinflammation, and Depression: An Overview of Pathophysiological Mechanisms and Emerging Anti-Inflammatories. Front. Psychiatry, 14.","DOI":"10.3389\/fpsyt.2023.1130989"},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Harsanyi, S., Kupcova, I., Danisovic, L., and Klein, M. (2022). Selected Biomarkers of Depression: What Are the Effects of Cytokines and Inflammation?. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms24010578"},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Eltokhi, A., and Sommer, I.E. (2022). A Reciprocal Link Between Gut Microbiota, Inflammation and Depression: A Place for Probiotics?. Front. Neurosci., 16.","DOI":"10.3389\/fnins.2022.852506"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1056\/NEJMra073096","article-title":"Major Depressive Disorder","volume":"358","author":"Belmaker","year":"2025","journal-title":"N. Engl. J. Med."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"339","DOI":"10.1038\/s41380-019-0474-5","article-title":"Peripheral Cytokine Levels and Response to Antidepressant Treatment in Depression: A Systematic Review and Meta-Analysis","volume":"25","author":"Liu","year":"2020","journal-title":"Mol. Psychiatry"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"03946320231198828","DOI":"10.1177\/03946320231198828","article-title":"Evaluation of Inflammatory Cytokines in Drug-Na\u00efve Major Depressive Disorder: A Systematic Review and Meta-Analysis","volume":"37","author":"Islam","year":"2023","journal-title":"Int. J. Immunopathol. Pharmacol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"547","DOI":"10.1016\/j.bbi.2020.04.039","article-title":"Altered Peripheral Blood Compounds in Drug-Naive First-Episode Patients with Either Schizophrenia or Major Depressive Disorder: A Meta-Analysis","volume":"88","author":"Sutterland","year":"2020","journal-title":"Brain Behav. Immun."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"6072","DOI":"10.1002\/sim.3427","article-title":"Meta-Analysis of Skewed Data: Combining Results Reported on Log-Transformed or Raw Scales","volume":"27","author":"Higgins","year":"2008","journal-title":"Stat. Med."},{"key":"ref_22","unstructured":"University, H.K.B. (2025, March 31). Mean Variance Estimation Calculator. Available online: https:\/\/www.math.hkbu.edu.hk\/~tongt\/papers\/median2mean.html."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1785","DOI":"10.1177\/0962280216669183","article-title":"Optimally Estimating the Sample Mean from the Sample Size, Median, Mid-Range, and\/or Mid-Quartile Range","volume":"27","author":"Luo","year":"2018","journal-title":"Stat. Methods Med. Res."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Wan, X., Wang, W., Liu, J., and Tong, T. (2014). Estimating the Sample Mean and Standard Deviation from the Sample Size, Median, Range and\/or Interquartile Range. BMC Med. Res. Methodol., 14.","DOI":"10.1186\/1471-2288-14-135"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"e1230","DOI":"10.1002\/cl2.1230","article-title":"PRISMA2020: An R Package and Shiny App for Producing PRISMA 2020-Compliant Flow Diagrams, with Interactivity for Optimised Digital Transparency and Open Synthesis","volume":"18","author":"Haddaway","year":"2022","journal-title":"Campbell Syst. Rev."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"76396","DOI":"10.1155\/2007\/76396","article-title":"Pro- and Anti-Inflammatory Cytokine Balance in Major Depression: Effect of Sertraline Therapy","volume":"2007","author":"Sutcigil","year":"2007","journal-title":"Clin. Dev. Immunol."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Tao, H., Chen, X., Zhou, H.F., Fu, J.H., Yu, Q., and Liu, Y. (2020). Changes of Serum Melatonin, Interleukin-6, Homocysteine, and Complement C3 and C4 Levels in Patients with Depression. Front. Psychol., 11.","DOI":"10.3389\/fpsyg.2020.01271"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"6724881","DOI":"10.1155\/2022\/6724881","article-title":"Associations between Autoimmunity and Depression: Serum IL-6 and IL-17 Have Directly Impact on the HAMD Scores in Patients with First-Episode Depressive Disorder","volume":"2022","author":"Mao","year":"2022","journal-title":"J. Immunol. Res."},{"key":"ref_29","first-page":"89","article-title":"Investigation of the Relationship between Inflammation and Oxidative Stress Markers and Treatment Response in First-Attack Major Depression Patients: A Follow-Up Study","volume":"34","author":"Emekdar","year":"2023","journal-title":"Turk. Psikiyatr. Derg."},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Xi, Y.Q., Wang, Z.Q., Li, G.J., Hao, Z.Q., Nie, J.H., Li, J.X., Tan, Y.T., Hu, X.D., Wang, G.W., and Liu, S. (2025). Association of Inflammation Cytokines with Cognitive Function in First-Episode Major Depressive Disorder. Front. Psychiatry, 15.","DOI":"10.3389\/fpsyt.2024.1473418"},{"key":"ref_31","first-page":"e3868","article-title":"Evaluation of Serum Interleukin-6 and C-Reactive Protein Levels in Drug-Naive Major Depressive Disorder Patients","volume":"11","author":"Nishuty","year":"2019","journal-title":"Cureus J. Med. Sci."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1080\/15622975.2019.1612090","article-title":"Lowered Zinc and Copper Levels in Drug-Naive Patients with Major Depression: Effects of Antidepressants, Ketoprofen and Immune Activation","volume":"21","author":"Twayej","year":"2020","journal-title":"World J. Biol. Psychiatry"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"44","DOI":"10.2174\/1871527319666200102100307","article-title":"Plasma Indoleamine-2,3-Dioxygenase (IDO) Is Increased in Drug-Naive Major Depressed Patients and Treatment with Sertraline and Ketoprofen Normalizes IDO in Association with Pro-Inflammatory and Immune-Regulatory Cytokines","volume":"19","author":"Twayej","year":"2020","journal-title":"CNS Neurol. Disord.-Drug Targets"},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Kim, J., Kim, J.H., and Chang, K.A. (2021). Sex Difference in Peripheral Inflammatory Biomarkers in Drug-Naive Patients with Major Depression in Young Adulthood. Biomedicines, 9.","DOI":"10.3390\/biomedicines9070708"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"238","DOI":"10.1016\/j.bbi.2021.03.022","article-title":"Inflammatory Cytokines, Complement Factor H and Anhedonia in Drug-Naive Major Depressive Disorder","volume":"95","author":"Tang","year":"2021","journal-title":"Brain Behav. Immun."},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Chen, L.P., Zeng, X.L., Zhou, S.J., Gu, Z.W., and Pan, J.Y. (2022). Correlation Between Serum High-Sensitivity C-Reactive Protein, Tumor Necrosis Factor-Alpha, Serum Interleukin-6 and White Matter Integrity Before and After the Treatment of Drug-Naive Patients with Major Depressive Disorder. Front. Neurosci., 16.","DOI":"10.3389\/fnins.2022.948637"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1016\/j.jad.2024.09.172","article-title":"The Relationship Between Plasma Interleukin-6 and Cognition Based on Curve Correlation in Drug-Na\u00efve Patients with Major Depressive Disorder","volume":"369","author":"Wang","year":"2025","journal-title":"J. Affect. Disord."},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Zou, W., Feng, R.J., and Yang, Y. (2018). Changes in the Serum Levels of Inflammatory Cytokines in Antidepressant Drug-Na\u00efve Patients with Major Depression. PLoS ONE, 13.","DOI":"10.1371\/journal.pone.0197267"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"114","DOI":"10.4103\/0253-7176.178772","article-title":"Is Depression an Inflammatory Disease? Findings from a Cross-Sectional Study at a Tertiary Care Center","volume":"38","author":"Muthuramalingam","year":"2016","journal-title":"Indian J. Psychol. Med."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"334","DOI":"10.4103\/psychiatry.IndianJPsychiatry_169_18","article-title":"C-Reactive Protein, Brain-Derived Neurotrophic Factor, Interleukin-2, and Stressful Life Events in Drug-Naive First-Episode and Recurrent Depression: A Cross-Sectional Study","volume":"60","author":"Jeenger","year":"2018","journal-title":"Indian. J. Psychiatry"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"327","DOI":"10.1016\/j.jad.2021.03.036","article-title":"The Relationship between Plasma Cytokine Levels and Antidepressant Response in Patients with First-Episode Major Depressive Disorder","volume":"287","author":"Lan","year":"2021","journal-title":"J. Affect. Disord."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"174","DOI":"10.1016\/j.jpsychires.2021.01.018","article-title":"Interleukin-1 Family and Serotonin Transporter in First-Episode, Drug-Naive Major Depressive Disorder: A Pilot Study","volume":"135","author":"Yang","year":"2021","journal-title":"J. Psychiatr. Res."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1621","DOI":"10.1007\/s00702-008-0115-7","article-title":"Antidepressant-like Activity of Zinc: Further Behavioral and Molecular Evidence","volume":"115","author":"Legutko","year":"2008","journal-title":"J. Neural Transm."},{"key":"ref_44","first-page":"4195","article-title":"Peripheral Alterations in Cytokine and Chemokine Levels After Antidepressant Drug Treatment for Major Depressive Disorder: Systematic Review and Meta-Analysis","volume":"55","author":"Freitas","year":"2018","journal-title":"Mol. Neurobiol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"8885","DOI":"10.1007\/s12035-018-1016-x","article-title":"The Compensatory Immune-Regulatory Reflex System (CIRS) in Depression and Bipolar Disorder","volume":"55","author":"Maes","year":"2018","journal-title":"Mol. Neurobiol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"373","DOI":"10.1111\/acps.12698","article-title":"Peripheral Cytokine and Chemokine Alterations in Depression: A Meta-Analysis of 82 Studies","volume":"135","author":"Freitas","year":"2017","journal-title":"Acta Psychiatr. Scand."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"516","DOI":"10.1176\/appi.ajp.20250289","article-title":"Advancing an Inflammatory Subtype of Major Depression","volume":"182","author":"Miller","year":"2025","journal-title":"Am. J. Psychiatry"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"154","DOI":"10.1016\/j.jad.2025.03.162","article-title":"Diet Quality and Depression Risk: A Systematic Review and Meta-Analysis of Prospective Studies","volume":"382","author":"Molero","year":"2025","journal-title":"J. Affect. Disord."},{"key":"ref_49","doi-asserted-by":"crossref","unstructured":"Du, Y., Dou, Y., Wang, M., Wang, Y., Yan, Y., Fan, H., Fan, N., Yang, X., and Ma, X. (2024). Efficacy and Acceptability of Anti-Inflammatory Agents in Major Depressive Disorder: A Systematic Review and Meta-Analysis. Front. Psychiatry, 15.","DOI":"10.3389\/fpsyt.2024.1407529"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"732","DOI":"10.1007\/s11596-016-1653-0","article-title":"Effects of IL-6 and Cortisol Fluctuations in Post-Stroke Depression","volume":"36","author":"Zhang","year":"2016","journal-title":"J. Huazhong Univ. Sci. Technol. [Med. Sci.]"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"e2588","DOI":"10.1002\/hup.2588","article-title":"Altered Serum Levels of TNF-\u03b1, IL-6, and IL-18 in Depressive Disorder Patients","volume":"32","author":"Fan","year":"2017","journal-title":"Hum. Psychopharmacol."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"2508","DOI":"10.1017\/S0033291718000090","article-title":"Association between Increased Serum Interleukin-6 Levels and Sustained Attention Deficits in Patients with Major Depressive Disorder","volume":"48","author":"Ye","year":"2018","journal-title":"Psychol. Med."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"206","DOI":"10.1016\/j.bbi.2015.06.001","article-title":"Cumulative Meta-Analysis of Interleukins 6 and 1\u03b2, Tumour Necrosis Factor \u03b1 and C-Reactive Protein in Patients with Major Depressive Disorder","volume":"49","author":"Haapakoski","year":"2015","journal-title":"Brain Behav. Immun."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"301","DOI":"10.1016\/0165-0327(95)00028-L","article-title":"Increased Plasma Concentrations of Interleukin-6, Soluble Interleukin-6, Soluble Interleukin-2 and Transferrin Receptor in Major Depression","volume":"34","author":"Maes","year":"1995","journal-title":"J. Affect. Disord."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"853","DOI":"10.1006\/cyto.1997.0238","article-title":"INCREASED SERUM IL-6 AND IL-1 RECEPTOR ANTAGONIST CONCENTRATIONS IN MAJOR DEPRESSION AND TREATMENT RESISTANT DEPRESSION","volume":"9","author":"Maes","year":"1997","journal-title":"Cytokine"},{"key":"ref_56","doi-asserted-by":"crossref","unstructured":"Kakeda, S., Watanabe, K., Katsuki, A., Sugimoto, K., Igata, N., Ueda, I., Igata, R., Abe, O., Yoshimura, R., and Korogi, Y. (2018). Relationship between Interleukin (IL)-6 and Brain Morphology in Drug-Naive, First-Episode Major Depressive Disorder Using Surface-Based Morphometry. Sci. Rep., 8.","DOI":"10.1038\/s41598-018-28300-5"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1016\/j.jad.2022.02.020","article-title":"Childhood Trauma and the Plasma Levels of IL-6, TNF-\u03b1 Are Risk Factors for Major Depressive Disorder and Schizophrenia in Adolescents: A Cross-Sectional and Case-Control Study","volume":"305","author":"Li","year":"2022","journal-title":"J. Affect. Disord."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"270","DOI":"10.1016\/j.psychres.2017.03.012","article-title":"Interleukin-6 and Depressive Symptom Severity in Response to Physical Exercise","volume":"252","author":"Lavebratt","year":"2017","journal-title":"Psychiatry Res."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"74","DOI":"10.1016\/j.psychres.2011.12.007","article-title":"Serum Concentrations of CRP, IL-6, TNF-\u03b1 and Cortisol in Major Depressive Disorder with Melancholic or Atypical Features","volume":"198","author":"Serretti","year":"2012","journal-title":"Psychiatry Res."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"2452","DOI":"10.1038\/npp.2011.132","article-title":"The Effect of Antidepressant Medication Treatment on Serum Levels of Inflammatory Cytokines: A Meta-Analysis","volume":"36","author":"Hannestad","year":"2011","journal-title":"Neuropsychopharmacology"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"119","DOI":"10.30773\/pi.2024.0295","article-title":"Differences Between Adolescent Depression and Healthy Controls in Biomarkers Associated with Immune or Inflammatory Processes: A Systematic Review and Meta-Analysis","volume":"22","author":"Li","year":"2025","journal-title":"Psychiatry Investig."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"48","DOI":"10.1016\/j.jad.2024.11.071","article-title":"Blood Cytokines in Major Depressive Disorder in Drug-Na\u00efve Adolescents: A Systematic Review and Meta-Analysis","volume":"372","author":"Jadhav","year":"2025","journal-title":"J. Affect. Disord."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"2632010X231180797","DOI":"10.1177\/2632010X231180797","article-title":"Elevated Serum IL-2 Levels Are Associated with Major Depressive Disorder: A Case-Control Study","volume":"16","author":"Suhee","year":"2023","journal-title":"Clin. Pathol."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"107042","DOI":"10.1016\/j.psyneuen.2024.107042","article-title":"Association between Peripheral Plasma Cytokine Levels and Suicidal Ideation in First-Episode, Drug-Na\u00efve Major Depressive Disorder","volume":"165","author":"Tian","year":"2024","journal-title":"Psychoneuroendocrinology"},{"key":"ref_65","doi-asserted-by":"crossref","unstructured":"Himmerich, H., Patsalos, O., Lichtblau, N., Ibrahim, M.A.A., and Dalton, B. (2019). Cytokine Research in Depression: Principles, Challenges, and Open Questions. Front. Psychiatry, 10.","DOI":"10.3389\/fpsyt.2019.00030"},{"key":"ref_66","doi-asserted-by":"crossref","unstructured":"Sarmin, N., Roknuzzaman, A.S.M., Mouree, T.Z., Islam, M.R., and Al Mahmud, Z. (2024). Evaluation of Serum Interleukin-12 and Interleukin-4 as Potential Biomarkers for the Diagnosis of Major Depressive Disorder. Sci. Rep., 14.","DOI":"10.1038\/s41598-024-51932-9"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"2045125320916655","DOI":"10.1177\/2045125320916655","article-title":"Altered Serum Interleukin-7 and Interleukin-10 Are Associated with Drug-Free Major Depressive Disorder","volume":"10","author":"Anjum","year":"2020","journal-title":"Ther. Adv. Psychopharmacol."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"296","DOI":"10.1590\/1516-4446-2014-1452","article-title":"Association of Interleukin-10 Levels with Age of Onset and Duration of Illness in Patients with Major Depressive Disorder","volume":"37","author":"Gazal","year":"2015","journal-title":"Braz. J. Psychiatry"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1016\/j.psyneuen.2014.03.019","article-title":"The Plasma Levels of Various Cytokines Are Increased during Ongoing Depression and Are Reduced to Normal Levels after Recovery","volume":"45","author":"Dahl","year":"2014","journal-title":"Psychoneuroendocrinology"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"2050312120974169","DOI":"10.1177\/2050312120974169","article-title":"Serum Interferon-Gamma Level Is Associated with Drug-Naive Major Depressive Disorder","volume":"8","author":"Daria","year":"2020","journal-title":"SAGE Open Med."},{"key":"ref_71","doi-asserted-by":"crossref","unstructured":"Ng, A., Tam, W.W., Zhang, M.W., Ho, C.S., Husain, S.F., McIntyre, R.S., and Ho, R.C. (2018). IL-1\u03b2, IL-6, TNF-\u03b1 and CRP in Elderly Patients with Depression or Alzheimer\u2019s Disease: Systematic Review and Meta-Analysis. Sci. Rep., 8.","DOI":"10.1038\/s41598-018-30487-6"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"92","DOI":"10.1016\/j.psychres.2009.03.023","article-title":"Transforming Growth Factor-\u03921 and Major Depressive Disorder with and without Attempted Suicide: Preliminary Study","volume":"178","author":"Lee","year":"2010","journal-title":"Psychiatry Res."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"1913","DOI":"10.1111\/ejn.15992","article-title":"Pro-Inflammatory Cytokines IL-1\u03b1, IL-6 and TNF-\u03b1 in Major Depressive Disorder: Sex-Specific Associations with Psychological Symptoms","volume":"57","author":"Elgellaie","year":"2023","journal-title":"Eur. J. Neurosci."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"418","DOI":"10.1016\/j.jpsychires.2025.02.062","article-title":"The Change of Inflammatory Cytokines after Antidepressant Treatment and Correlation with Depressive Symptoms","volume":"184","author":"Yin","year":"2025","journal-title":"J. Psychiatr. Res."},{"key":"ref_75","doi-asserted-by":"crossref","unstructured":"G\u0119dek, A., Szular, Z., Antosik, A.Z., Mierzejewski, P., and Dominiak, M. (2023). Celecoxib for Mood Disorders: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. J. Clin. Med., 12.","DOI":"10.3390\/jcm12103497"},{"key":"ref_76","doi-asserted-by":"crossref","unstructured":"Dominiak, M., G\u0119dek, A., Sikorska, M., Mierzejewski, P., Wojnar, M., and Antosik-W\u00f3jci\u0144ska, A.Z. (2022). Acetylsalicylic Acid and Mood Disorders: A Systematic Review. Pharmaceuticals, 16.","DOI":"10.3390\/ph16010067"},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"335","DOI":"10.1038\/mp.2016.167","article-title":"Antidepressant Activity of Anti-Cytokine Treatment: A Systematic Review and Meta-Analysis of Clinical Trials of Chronic Inflammatory Conditions","volume":"23","author":"Kappelmann","year":"2018","journal-title":"Mol. Psychiatry"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"379","DOI":"10.1111\/j.1600-0447.1991.tb03163.x","article-title":"Depression-Related Disturbances in Mitogen-Induced Lymphocyte Responses and Interleukin-1\u03b2 and Soluble Interleukin-2 Receptor Production","volume":"84","author":"Maes","year":"1991","journal-title":"Acta Psychiatr. Scand."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"397","DOI":"10.1002\/hup.609","article-title":"Cytokines: Abnormalities in Major Depression and Implications for Pharmacological Treatment","volume":"19","author":"Scott","year":"2004","journal-title":"Hum. Psychopharmacol. Clin. Exp."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"248","DOI":"10.1192\/apt.bp.106.003319","article-title":"Inflammation and Its Relevance to Psychiatry","volume":"14","author":"Cavanagh","year":"2008","journal-title":"Adv. Psychiatr. Treat."},{"key":"ref_81","first-page":"269","article-title":"Brain Corticosteroid Receptor Balance in Health and Disease","volume":"19","author":"Vreugdenhil","year":"1998","journal-title":"Endocr. Rev."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"464","DOI":"10.1016\/j.tins.2008.06.006","article-title":"The HPA Axis in Major Depression: Classical Theories and New Developments","volume":"31","author":"Pariante","year":"2008","journal-title":"Trends Neurosci."},{"key":"ref_83","first-page":"114","article-title":"Depression and Hypothalamic-Pituitary-Adrenal Activation: A Quantitative Summary of Four Decades of Research","volume":"73","author":"Stetler","year":"2011","journal-title":"Biopsychosoc. Sci. Med."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1016\/j.neulet.2008.06.007","article-title":"Induction of Indolamine 2,3-Dioxygenase and Kynurenine 3-Monooxygenase in Rat Brain Following a Systemic Inflammatory Challenge: A Role for IFN-Gamma?","volume":"441","author":"Connor","year":"2008","journal-title":"Neurosci. Lett."},{"key":"ref_85","first-page":"264","article-title":"Somatization, but Not Depression, Is Characterized by Disorders in the Tryptophan Catabolite (TRYCAT) Pathway, Indicating Increased Indoleamine 2,3-Dioxygenase and Lowered Kynurenine Aminotransferase Activity","volume":"32","author":"Maes","year":"2011","journal-title":"Neuro Endocrinol. Lett."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"592","DOI":"10.3109\/09540261.2013.813442","article-title":"Cytokines as Biomarkers in Depressive Disorder: Current Standing and Prospects","volume":"25","author":"Lichtblau","year":"2013","journal-title":"Int. Rev. Psychiatry"},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"e946","DOI":"10.1038\/tp.2016.212","article-title":"Neuropathology of Mood Disorders: Do We See the Stigmata of Inflammation?","volume":"6","author":"Mechawar","year":"2016","journal-title":"Transl. Psychiatry"},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"72","DOI":"10.1016\/j.psyneuen.2018.11.001","article-title":"Cross-Sectional Relationship between Kynurenine Pathway Metabolites and Cognitive Function in Major Depressive Disorder","volume":"101","author":"Zhou","year":"2019","journal-title":"Psychoneuroendocrinology"},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"732","DOI":"10.1016\/j.biopsych.2008.11.029","article-title":"Inflammation and Its Discontents: The Role of Cytokines in the Pathophysiology of Major Depression","volume":"65","author":"Miller","year":"2009","journal-title":"Biol. Psychiatry"},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"314","DOI":"10.1038\/s41398-025-03532-y","article-title":"Modulation of Neuroimmune Cytokine Networks by Antidepressants: Implications in Mood Regulation","volume":"15","author":"Nava","year":"2025","journal-title":"Transl. Psychiatry"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/21\/10362\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,27]],"date-time":"2025-10-27T00:52:45Z","timestamp":1761526365000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/21\/10362"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,10,24]]},"references-count":90,"journal-issue":{"issue":"21","published-online":{"date-parts":[[2025,11]]}},"alternative-id":["ijms262110362"],"URL":"https:\/\/doi.org\/10.3390\/ijms262110362","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,10,24]]}}}