Cortical brain morphology in early-onset psychosis (EOP; age of onset < 19 years) is poorly understood, partly due to recruitment constraints linked to its low incidence. We pooled T1-weighted magnetic resonance imaging (MRI) data from 387 adolescents with EOP (mean age=16.1±1.5; 49.6% female) and 338 healthy controls (CTR; mean age=15.8±1.9, 54.4% female) from nine research sites worldwide. Using harmonized processing protocols with FreeSurfer, we extracted cortical brain metrics from 34 bilateral regions. Univariate regression analysis revealed widespread lower bilateral cortical thickness (left/right hemisphere: d=-0.36/-0.31), surface area (left/right: d=-0.42/-0.41), cortical volume (left/right: d=-0.58/-0.56), and Local Gyrification Index (LGI; left/right: d=-0.39/-0.52) in EOP relative to CTR. Subgroup analyses showed broader and more pronounced case-control differences in early-onset schizophrenia for area, volume, and LGI. We found no associations with antipsychotic medication use, illness duration, age of onset, or positive symptoms. Negative symptoms were related to smaller left lingual volumes (partial r=-0.21; pFDR=0.014) and antidepressant users had smaller area (d=-0.43; pFDR=0.034) and volume (d=-0.50; pFDR=0.003) of the right rostral anterior cingulate compared to non-users. Cortical alterations in EOP showed a similar pattern to those observed in prior studies on adults with schizophrenia (SCZ; r=0.62) and bipolar disorders (BD; r=0.61). However, surface area alterations were overall 1.5 times greater for EOP than adult SCZ and 4.6 times greater than adult BD. In the largest study of its kind, we observed an extensive pattern of cortical alterations in adolescents with psychotic disorders, highlighting the potential impact of aberrant neurodevelopment on cortical morphology in this clinical group.

Ingrid Agartz: Has received a speaker's honorarium from Lundbeck. Inmaculada Baeza: Has received honoraria and travel support from Angelini and Otsuka-Lundbeck. Ole A. Andreassen: Has received a speaker's honorarium from Lundbeck Sunovion and is a consultant to HealthLytix. Adriana Fortea: Has received speaking fees and travel support from Viatris, Abbott and Otsuka-Lundbeck. Celso Arango: Has been a consultant to or has received honoraria or grants from Acadia, Angelini, Gedeon Richter, Janssen Cilag, Lundbeck, Medscape, Otsuka, Roche, Sage, Servier, Shire, Schering Plough, Sumitomo Dainippon Pharma, Sunovion, and Takeda. Covadonga M. Díaz-Caneja: Has received honoraria and/or travel support from Angelini, Johnson & Johnson, and Viatris.

The following research grants facilitated the study: ENIGMA - US National Institutes of Health (NIH): R01-EB015611, R01-MH116147 (Sex Differences, to PMT), R01-MH117601, S10-OD023696, R01-MH129742 (ENIGMA-Bipolar, to PMT), R01-MH134004. The ENIGMA Working Group acknowledges the NIH Big Data to Knowledge (BD2K) award for foundational support and consortium development (U54 EB020403 to PMT). For a complete list of ENIGMA-related grant support please see here: http://enigma.ini.usc.edu/about-2/funding/. BARCELONA - Spanish Ministry of Health, Instituto de Salud Carlos III "Health Research Fund"/FEDER funds: PI17/00741; PI18/00976, PI21/00519, PI20/00654, PI21/00330, FORT23/00002_SUGR_G6, PI24/00279; PI24/01052; Brain and Behaviour Research Foundation: 26731; Department of Health, Government of Catalonia: SLT006/17/00362; Marato TV3: 202232-30-31 and 202210-10; Alicia Koplowtiz Foundation; Pons Bartran Legacy: FCRB-IPB2-2023; Maria and Nuria Cunillera Legacies. MADRID - Spanish Ministry of Science and Innovation, Instituto de Salud Carlos III (ISCIII), co-financed by the European Union, ERDF Funds from the European Commission, "A way of making Europe": Redes Temáticas-ISCIII G03-032; RETICS (REM-TAP Network) RD06/0011, PS09/01442, PI12/1303, PI22/01824, PI22/01621, PI23/00625; Consorcio Centro Investigación Biomédica en Red (CIBER): CB/07/09/0023; European Union: FP7-HEALTH-2013-2.2.1-2-603196 (Project PSYSCAN), METSY: FP7-HEALTH-2013-2.2.1-2-602478 (Project METSY); Madrid Regional Government: S2010/BMD-2422, B2017/BMD-3740, S2022/BMD-7216 (AGES 3-CM); Fundación Familia Alonso: FIBHGM-CCA004-2018; Fundación Alicia Koplowitz: FAK13. ROME - Italian Ministry of Health: Ricerca Corrente 25. OXFORD - MRC G0500092. KCL-1 - Brain & Behavior Research Foundation (prev. NARSAD). KCL-2 - Dutch Research Council (NWO): VIDI 0452-07-007 (to LK). UCLA - National Institute of Mental Health: P50MH066286, U01MH081902. SCAPS - Swedish Research Council: 521‐2014‐3487, 2017‐00949; Formas: 259‐2012‐31. UIO-PSI - South‐Eastern Norway Regional Health Authority: 2004‐259, 2006‐186. YTOP: South-Eastern Norway Regional Health Authority: 2017-097, 2017-112, 2019-104, 2020-020, 2021-070, 2022-080, 2024-012; Research Council of Norway: 223273, 274359, 2137000, 250358, 288083, 323951; K. G. Jebsen Foundation: SKGJ-MED-008.

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

Yes

The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

The ENIGMA-EOP Working Group, coordinated by Stener Nerland, Claudia Barth, and Ingrid Agartz, obtained data from nine cohorts acquired in six countries. Approval was obtained from the Norwegian Regional Committees for Medical and Health Research Ethics (REK; #2009/691), the Norwegian Data Protection Authority (Datatilsynet; #2003/2052), and the Data Protection Officers (DPOs) of the Oslo University Hospital and Diakonhjemmet Hospital. For each research site, all study participants and/or their legal guardians provided written informed consent and all research sites obtained the appropriate approvals from their local IRBs. Participant identifiers were not shared with the coordinators of this study, so identification of individuals was not possible. The study was conducted in compliance with the General Data Protection Regulation (GDPR) and the Declaration of Helsinki revised in 2024.

I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.

Yes

I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

Yes

I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.

Yes

Data analyzed in the present study may be accessed upon reasonable request to the authors and the ENIGMA-EOP Working Group.