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Negative symptoms are associated with poor clinical and psychosocial outcome in schizophrenia. Their prevalence and identification in first-episode patients remains controversial. In a large cohort of patients in the early stage of schizophrenia, schizophreniform or schizoaffective disorder, we investigated, over the different phases of the OPTiMiSE trial (baseline, 4, 10 and 22 weeks of treatment), the prevalence of negative symptoms of moderate severity, unconfounded by depression and extrapyramidal symptoms at baseline. Moreover, we assessed symptomatic remission, attrition rate and psychosocial functioning in subjects with short-term (4 weeks) persistent unconfounded negative symptoms (PNS) and in those with negative symptoms that did not persist at follow-up and/or were confounded at baseline (N-PNS). Negative symptoms of moderate severity were observed in 59% of subjects at baseline. They were associated with worse psychosocial functioning and longer duration of psychosis at intake in the study. Eleven percent of subjects had PNS unconfounded at baseline and 7.9% had PNS unconfounded at both baseline and end of 4-week treatment. Psychosocial functioning was comparable in PNS and N-PNS subjects at baseline but it was significantly worse in the former group after 4-weeks. PNS subjects showed lower remission and higher attrition rates at the end of all treatment phases. Fifty-six percent of subjects completing phase 3 (clozapine treatment) had PNS, and 60% of them were non-remitters at the end of this phase. The presence of short-term PNS during the first phases of psychosis was associated with poor clinical outcome and resistance to antipsychotic treatment, including clozapine., Competing Interests: Declaration of Competing Interest C. Arango has been a consultant to or has received honoraria or grants from Acadia, Angelini, Gedeon Richter, Janssen Cilag, Lundbeck, Otsuka, Roche, Sage, Sanofi, Servier, Shire, Schering Plough, Sumitomo Dainippon Pharma, Sunovion and Takeda. R. Buchanan has served on an advisory board for Avanir, GW Pharma Ltd., Minerva, and Roche; and served on a DSMB for Roche. C.M. Díaz-Caneja has received honorary fees from Sanofi-Aventis and Abbvie, and grant support from Instituto de Salud Carlos III (Spanish Ministry of Science, Innovation and Universities). S. Galderisi has been a consultant and/or advisor to or has received honoraria or grants from: Millennium Pharmaceuticals, Innova Pharma-Recordati Group, Janssen Pharmaceutica NV, Sunovion Pharmarmaceuticals, Janssen–Cilag Polska Sp. zo. o., Gedeon Richter-Recordati, Pierre Fabre, Otsuka, Angelini. B. Glenthøj is the leader of a Lundbeck Foundation center of Excellence for Clinical Intervention and Neuropsychiatric Schizophrenia Research (CINS), which is partially financed by an independent grant from the Lundbeck Foundation based on international review and partially financed by the Mental Health Services in the Capital Region of Denmark, the University of Copenhagen, and other foundations. Her group has also received a research grant from Lundbeck A/S for another independent investigator-initiated study. 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. S. Leucht has received honoraria as a consultant/advisor and/or for lectures from LB Pharma, Otsuka, Lundbeck, Boehringer Ingelheim, LTS Lohmann, Janssen, Johnson&Johnson, TEVA, MSD, Sandoz, SanofiAventis, Angelini, Recordati, Sunovion, Geodon Richter. A. Mucci received honoraria, advisory board or consulting fees from the following companies: Amgen Dompé, Angelini-Acraf, Astra Zeneca, Bristol-Myers Squibb, Gedeon Richter Bulgaria, Innova-Pharma, Janssen Pharmaceuticals, Lundbeck, Otsuka, Pfizer and Pierre Fabre. R. Rodriguez-Jimenez has been a consultant for, spoken in activities of, or received grants from: Instituto de Salud Carlos III, Fondo de Investigación Sanitaria (FIS), Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Madrid Regional Government(S2010/ BMD-2422 AGES), JanssenCilag, Lundbeck, Otsuka, Pfizer, Ferrer, Juste, Takeda, Exeltis, Angelini. All other authors have no conflicts of interest to declare., (Copyright © 2020. Published by Elsevier B.V.)