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Epidemiological studies indicate that ~36% of patients with multimorbidity exhibit psychosomatic comorbidity, with higher risk populations concentrated among females, older adults, and socioeconomically disadvantaged individuals. This review systematically analyzes the epidemiological distribution patterns of MD\u2013CD comorbidity, with the strongest emphasis on cardiometabolic diseases\u2014diabetes, metabolic syndrome (MetS), obesity, hypertension (HTA), and cardiovascular disease (CVD)\u2014for which the mechanistic data are most developed, while also addressing osteoarthritis, psoriasis, inflammatory bowel disease (IBD), cancer, and neurological disorders. By integrating molecular mechanisms with clinical evidence, we highlight core pathological pathways and critically evaluate the strength of evidence supporting each: hypothalamic\u2013pituitary\u2013adrenal (HPA) axis dysfunction and insulin resistance (IR), substantiated by clinical data and Mendelian randomization; NLRP3 inflammasome\u2010mediated neuroinflammation as a transdiagnostic inflammatory node; gut\u2013brain axis dysregulation involving bile acid\u2013GLP\u20101 signaling and gut\u2010derived metabolites such as trimethylamine N\u2010oxide (TMAO); and the kynurenine pathway (KP) as a branched metabolite axis with organ\u2010specific consequences. Sex\u2010specific mechanisms, particularly estrogen\u2010regulated neuroendocrine and metabolic pathways, are identified as consistent biological modifiers of this comorbidity. A bidirectional vicious cycle underpins MD\u2013CD comorbidity: metabolic abnormalities exacerbate limbic system dysfunction via HPA\u2010axis hyperactivity, neuroinflammatory cascades, and disrupted gut\u2013brain signaling, while MDs aggravate metabolic dysregulation through neuroendocrine disturbances and reduced treatment adherence.<\/jats:p>","DOI":"10.1155\/da\/7688691","type":"journal-article","created":{"date-parts":[[2026,7,24]],"date-time":"2026-07-24T09:00:21Z","timestamp":1784883621000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Comorbidity Between Mood Disorders and Chronic Somatic Diseases, With a Focus on Cardiometabolic Disease, and Its Mechanistic Crosstalk"],"prefix":"10.1155","volume":"2026","author":[{"ORCID":"https:\/\/orcid.org\/0009-0001-5097-2735","authenticated-orcid":false,"given":"Hongzhen","family":"Du","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0992-2613","authenticated-orcid":false,"given":"Gangqiang","family":"Du","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qian","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yixuan","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9508-4766","authenticated-orcid":false,"given":"Jilin","family":"Fan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yufeng","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zihao","family":"Sun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5385-6249","authenticated-orcid":false,"given":"Chen","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6378-7723","authenticated-orcid":false,"given":"Wei","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,7,24]]},"reference":[{"key":"e_1_2_15_1_2","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1002\/wps.20825","article-title":"An Organization- and Category-Level Comparison of Diagnostic Requirements for Mental Disorders in ICD-11 and DSM-5","volume":"20","author":"First M. 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