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We show that all symptom domains (negative and PHEMFP) may be used to derive a single latent trait called overall severity of schizophrenia (OSOS). In addition, neurocognitive test results may be used to extract a general cognitive decline (G-CoDe) index, based on executive function, attention, semantic and episodic memory, and delayed recall scores. According to partial least squares analysis, the impacts of adverse outcome pathways (AOPs) on OSOS are partially mediated by increasing G-CoDe severity. The AOPs include neurotoxic cytokines and chemokines, oxidative damage to proteins and lipids, IgA responses to neurotoxic tryptophan catabolites, breakdown of the vascular and paracellular pathways with translocation of Gram-negative bacteria, and insufficient protection through lowered antioxidant levels and impairments in the innate immune system. Unsupervised machine learning identified a new schizophrenia endophenotype class, named major neurocognitive psychosis (MNP), which is characterised by increased negative symptoms and PHEMFP, G-CoDe and the above-mentioned AOPs. Based on these pathways and phenome features, MNP is a distinct endophenotype class which is qualitatively different from simple psychosis (SP). It is impossible to draw any valid conclusions from research on schizophrenia that ignores the MNP and SP distinctions.<\/jats:p>","DOI":"10.1017\/neu.2022.32","type":"journal-article","created":{"date-parts":[[2022,11,14]],"date-time":"2022-11-14T09:28:10Z","timestamp":1668418090000},"page":"123-137","update-policy":"https:\/\/doi.org\/10.1017\/policypage","source":"Crossref","is-referenced-by-count":20,"title":["Major neurocognitive psychosis: a novel schizophrenia endophenotype class that is based on machine learning and resembles Kraepelin\u2019s and Bleuler\u2019s conceptions"],"prefix":"10.1017","volume":"35","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2012-871X","authenticated-orcid":false,"given":"Michael","family":"Maes","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"56","published-online":{"date-parts":[[2022,11,14]]},"reference":[{"key":"S0924270822000321_ref67","first-page":"1","volume-title":"Biochemistry, Schizophrenia, and Affective Illness","author":"Snezhnevsky","year":"1970"},{"key":"S0924270822000321_ref28","doi-asserted-by":"publisher","DOI":"10.1007\/s11747-014-0403-8"},{"key":"S0924270822000321_ref4","doi-asserted-by":"publisher","DOI":"10.1016\/j.jad.2021.03.062"},{"key":"S0924270822000321_ref10","doi-asserted-by":"publisher","DOI":"10.1136\/bmj.d556"},{"key":"S0924270822000321_ref73","doi-asserted-by":"publisher","DOI":"10.1016\/j.compedu.2011.06.008"},{"key":"S0924270822000321_ref34","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0197004"},{"key":"S0924270822000321_ref75","doi-asserted-by":"publisher","DOI":"10.1016\/j.pnpbp.2010.08.018"},{"key":"S0924270822000321_ref23","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(18)32279-7"},{"key":"S0924270822000321_ref27","doi-asserted-by":"publisher","DOI":"10.1016\/j.schres.2003.08.007"},{"key":"S0924270822000321_ref72","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.b.32161"},{"key":"S0924270822000321_ref2","doi-asserted-by":"publisher","DOI":"10.1007\/s12640-019-00112-z"},{"key":"S0924270822000321_ref7","doi-asserted-by":"publisher","DOI":"10.1192\/S0007125000291496"},{"key":"S0924270822000321_ref69","doi-asserted-by":"publisher","DOI":"10.1007\/s12640-019-00139-2"},{"key":"S0924270822000321_ref70","doi-asserted-by":"publisher","DOI":"10.5498\/wjp.v11.i1.1"},{"key":"S0924270822000321_ref3","doi-asserted-by":"publisher","DOI":"10.1017\/S1092852920001182"},{"key":"S0924270822000321_ref46","doi-asserted-by":"publisher","DOI":"10.1007\/s12035-018-1437-6"},{"volume-title":"Symptoms of Psychosis","year":"2022","key":"S0924270822000321_ref18"},{"key":"S0924270822000321_ref1","doi-asserted-by":"publisher","DOI":"10.2174\/1568026620666200128143948"},{"key":"S0924270822000321_ref31","doi-asserted-by":"publisher","DOI":"10.1111\/jep.12945"},{"key":"S0924270822000321_ref19","doi-asserted-by":"crossref","first-page":"191","DOI":"10.4103\/0019-5545.64591","article-title":"Emil Kraepelin: a pioneer of scientific understanding of psychiatry and psychopharmacology","volume":"52","author":"Ebert","year":"2010","journal-title":"Indian Journal of Psychiatry"},{"key":"S0924270822000321_ref29","doi-asserted-by":"publisher","DOI":"10.1177\/1359786810385490"},{"key":"S0924270822000321_ref35","unstructured":"Karsner, D (2022) Restriction of Range: Definition & Examples. 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