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The kynurenine and serotonin pathways, as well as chronic low-grade inflammation, are being considered potential links between them. MDD associated with T2DM is less responsive to treatment than that without T2DM; however, the underlying mechanism remains unknown. We aimed to investigate the effects of inflammatory cytokines on the kynurenine and serotonin pathways in patients with comorbid MDD and T2DM and those with only MDD. We recruited 13 patients with comorbid MDD and T2DM and 27 patients with only\u00a0MDD. We measured interleukin-6 and tumor necrosis factor-\u03b1 (TNF-\u03b1) levels as inflammatory cytokines and metabolites of the kynurenine pathway and examined the relationship between the two. TNF-\u03b1 levels were significantly higher in patients with comorbid MDD and T2DM than in those with only MDD in univariate (p\u2009=\u20090.044) and multivariate (adjusted p\u2009=\u20090.036) analyses. TNF-\u03b1 showed a statistically significant effect modification (interaction) with quinolinic acid\/tryptophan and serotonin in patients from both groups (\u03b2\u2009=\u20091.029, adjusted p\u2009&lt;\u20090.001; \u03b2\u2009=\u2009\u2009\u2212\u20091.444, adjusted p\u2009=\u20090.047, respectively). Limitations attributed to the study design and number of samples may be present. All patients were Japanese with mild to moderate MDD; therefore, the generalizability of our findings may be limited. MDD with T2DM has more inflammatory depression components and activations of the kynurenine pathway by inflammatory cytokines than MDD without T2DM. Hence, administering antidepressants and anti-inflammatory drugs in combination may be more effective in patients with comorbid MDD and T2DM.<\/jats:p>","DOI":"10.1007\/s00406-023-01713-8","type":"journal-article","created":{"date-parts":[[2023,11,22]],"date-time":"2023-11-22T14:05:47Z","timestamp":1700661947000},"page":"1697-1707","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":20,"title":["Effect modification of tumor necrosis factor-\u03b1 on the kynurenine and serotonin pathways in major depressive disorder on type 2 diabetes mellitus"],"prefix":"10.1007","volume":"274","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2791-8113","authenticated-orcid":false,"given":"Naomichi","family":"Okamoto","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takashi","family":"Hoshikawa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuichi","family":"Honma","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Enkhmurun","family":"Chibaatar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Atsuko","family":"Ikenouchi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masaru","family":"Harada","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Reiji","family":"Yoshimura","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2023,11,22]]},"reference":[{"key":"1713_CR1","doi-asserted-by":"publisher","unstructured":"Ikenouchi A, Okamoto N, Igata R, et al (2022) The molecular mechanism of exercise for treatment of patients with major depression: a preliminary report on the dynamics of metabolites of nitric oxide and catecholamines. 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