{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,4]],"date-time":"2026-08-04T13:45:14Z","timestamp":1785851114688,"version":"3.56.0"},"reference-count":94,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2020,8,26]],"date-time":"2020-08-26T00:00:00Z","timestamp":1598400000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Diagnostics"],"abstract":"<jats:p>Background: activation of the immune-inflammatory response system (IRS) and the compensatory immune-regulatory system (CIRS) plays a key role in schizophrenia (SCZ) and treatment resistant SCZ. There are only a few data on immune and endogenous opioid system (EOS) interactions in SCZ and treatment resistant SCZ. Methods: we examined serum \u03b2-endorphin, endomorphin-2 (EM2), mu-opioid (MOR) and kappa-opioid (KOR) receptors, and interleukin (IL)-6 and IL-10 in 60 non responders to treatment (NRTT), 55 partial RTT (PRTT) and 43 normal controls. Results: serum EM2, KOR, MOR, IL-6 and IL-10 were significantly increased in SCZ as compared with controls. \u03b2-endorphin, EM2, MOR and IL-6 were significantly higher in NRTT than in PRTT. There were significant correlations between IL-6, on the one hand, and \u03b2-endorphin, EM2, KOR, and MOR, on the other, while IL-10 was significantly correlated with MOR only. A large part of the variance in negative symptoms, psychosis, hostility, excitation, mannerism, psychomotor retardation and formal thought disorders was explained by the combined effects of EM2 and MOR with or without IL-6 while increased KOR was significantly associated with all symptom dimensions. Increased MOR, KOR, EM2 and IL-6 were also associated with neurocognitive impairments including in episodic, semantic and working memory and executive functions. Conclusion: the EOS contributes to SCZ symptomatology, neurocognitive impairments and a non-response to treatment. In SCZ, EOS peptides\/receptors may exert CIRS functions, whereas increased KOR levels may contribute to the pathophysiology of SCZ and EM2 and KOR to a non-response to treatment.<\/jats:p>","DOI":"10.3390\/diagnostics10090633","type":"journal-article","created":{"date-parts":[[2020,8,26]],"date-time":"2020-08-26T09:05:37Z","timestamp":1598432737000},"page":"633","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["The Endogenous Opioid System in Schizophrenia and Treatment Resistant Schizophrenia: Increased Plasma Endomorphin 2, and \u03ba and \u03bc Opioid Receptors Are Associated with Interleukin-6"],"prefix":"10.3390","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3125-7373","authenticated-orcid":false,"given":"Shatha Rouf","family":"Moustafa","sequence":"first","affiliation":[{"name":"Clinical Analysis Department, College of Pharmacy, Hawler Medical University, Havalan City, Erbil 44001, Iraq"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Khalid F.","family":"Al-Rawi","sequence":"additional","affiliation":[{"name":"College of Science, University of Anbar, Ramadi 31001, Iraq"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9975-3680","authenticated-orcid":false,"given":"Drozdstoi","family":"Stoyanov","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, Medical University of Plovdiv, Plovdiv 4000, Bulgaria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arafat Hussein","family":"Al-Dujaili","sequence":"additional","affiliation":[{"name":"Clinical Psychiatry, Faculty of Medicine, University of Kufa, Najaf 540011, Iraq"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6555-0781","authenticated-orcid":false,"given":"Thitiporn","family":"Supasitthumrong","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, Faculty of Medicine, Chulalongkorn University, Bangkok 10110, Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6143-5196","authenticated-orcid":false,"given":"Hussein Kadhem","family":"Al-Hakeim","sequence":"additional","affiliation":[{"name":"Department of Chemistry, College of Science, University of Kufa, Najaf 540011, Iraq"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Maes","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, Medical University of Plovdiv, Plovdiv 4000, Bulgaria"},{"name":"Department of Psychiatry, Faculty of Medicine, Chulalongkorn University, Bangkok 10110, Thailand"},{"name":"School of Medicine, IMPACT Strategic Research Centre, Deakin University, Geelong, VIC 3220, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,8,26]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1016\/0306-9877(95)90062-4","article-title":"The macrophage-T-lymphocyte theory of schizophrenia: Additional evidence","volume":"45","author":"Smith","year":"1995","journal-title":"Med. 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