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In support, we have previously shown that aberrant interrelations between these neurotransmitters, in contrast to individual transmitter systems, can separate antipsychotic-na\u00efve first-episode psychotic patients (AN-FEP) from healthy controls (HC). Here, we characterized neurotransmitter interrelations, examined their association with treatment response, and explored the effect of treatment on the interrelations. Sixty participants (29 AN-FEP and 31 HC) underwent dynamic [18F]-DOPA PET with arterial blood sampling to measure dopamine synthesis (DS) (k\n                    <jats:sub>3<\/jats:sub>\n                    ) in nucleus accumbens (NAcc) and magnetic resonance spectroscopy (MRS) to estimate levels of glutamate (Glu) in anterior cingulate cortex (ACC) and thalamus, and gamma-aminobutyric-acid (GABA) in ACC. A subgroup of the patients was re-scanned after six weeks antipsychotic monotherapy with aripiprazole (PET: 10 AN-FEP; MRS: 27 AN-FEP; 30 HC). Psychopathology was assessed at both visits. Multiple linear regression models and linear mixed models were used to analyze data. We found a negative association between k\n                    <jats:sub>3<\/jats:sub>\n                    (dependent variable) and GABA in HC (\u03b2\u2009=\u2009\u22120.15, p\u2009=\u20090.03) and a positive association in patients (\u03b2\u2009=\u20090.15, p\u2009=\u20090.04). The aberrant relationship between k\n                    <jats:sub>3<\/jats:sub>\n                    and GABA was driven by the group-GABA interaction (p\u2009=\u20090.002) and related to treatment response (p\u2009=\u20090.02). No significant group interactions were found for the interrelations between k\n                    <jats:sub>3<\/jats:sub>\n                    and Glu, but a positive association was found between k\n                    <jats:sub>3<\/jats:sub>\n                    and Glu in thalamus (p\u2009=\u20090.04) in both groups and the association decreased after treatment in AN-FEP (p\u2009=\u20090.01). The data show that DS in NAcc and GABA levels in ACC are inversely interrelated in AN-FEP, and that the degree of abnormality predicts treatment effect. Moreover, antipsychotic treatment alters the relationship between dopaminergic activity in NAcc and Glu levels in thalamus. The findings suggest that combined instead of single neurotransmitter disturbances should be considered when novel therapeutics are developed for schizophrenia. Clinical trial registration: The Pan European Collaboration on Antipsychotic Na\u00efve Schizophrenia II (PECANSII) study, ClinicalTrials.gov Identifier: NCT02339844.\n                    <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"https:\/\/www.clinicaltrials.gov\/study\/NCT02339844\" ext-link-type=\"uri\">https:\/\/www.clinicaltrials.gov\/study\/NCT02339844<\/jats:ext-link>\n                    .\n                  <\/jats:p>","DOI":"10.1038\/s41380-025-03229-0","type":"journal-article","created":{"date-parts":[[2025,9,12]],"date-time":"2025-09-12T14:06:25Z","timestamp":1757685985000},"page":"1231-1240","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Interrelations between dopaminergic-, gabaergic- and glutamatergic neurotransmitters in antipsychotic-na\u00efve psychosis patients and the association to initial treatment response"],"prefix":"10.1038","volume":"31","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7996-3154","authenticated-orcid":false,"given":"Kirsten Borup","family":"Bojesen","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5638-2357","authenticated-orcid":false,"given":"Karen S.","family":"Ambrosen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anne Korning","family":"Sigvard","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mette \u00d8degaard","family":"Nielsen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Albert","family":"Gjedde","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoshitaka","family":"Kumakura","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lars Thorbj\u00f8rn","family":"Jensen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8926-3549","authenticated-orcid":false,"given":"Dan","family":"Fugl\u00f8","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2590-5055","authenticated-orcid":false,"given":"Bj\u00f8rn Hylsebeck","family":"Ebdrup","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Egill","family":"Rostrup","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3056-7262","authenticated-orcid":false,"given":"Birte Yding","family":"Glenth\u00f8j","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,9,12]]},"reference":[{"key":"3229_CR1","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1016\/0893-133X(88)90012-7","volume":"1","author":"A Carlsson","year":"1988","unstructured":"Carlsson A. 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All grants are the property of the Mental Health Services in the Capital Region of Denmark and administrated by them. She has no other conflicts to disclose. Dr. Bojesen received lecture fees from Lundbeck Pharma A\/S. Dr. Ebdrup BE is part of the Advisory Board of Boehringer Ingelheim, Lundbeck Pharma A\/S; and has received lecture fees from Boehringer Ingelheim, Otsuka Pharma Scandinavia AB, and Lundbeck Pharma A\/S. The rest of the authors have no conflicts of interest to disclose.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}]}}