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Brain ageing in schizophrenia: evidence from 26 international cohorts via the ENIGMA Schizophrenia consortium

Constantinides, C., Han, L. K. M., Alloza, C. , Antonucci, L. A., Arango, C., Ayesa-Arriola, R., Banaj, N., Bertolino, A., Borgwardt, S., Bruggemann, J., Bustillo, J., Bykhovski, O., Calhoun, V., Carr, V., Catts, S., Chung, Y-C., Crespo-Facorro, B., Díaz-Caneja, C. M., Donohoe, G., Plessis, S. D., Edmond, J., Ehrlich, S., Emsley, R., Eyler, L. T., Fuentes-Claramonte, P., Georgiadis, F., Green, M., Guerrero-Pedraza, A., Ha, M., Hahn, T., Henskens, F. A., Holleran, L., Homan, S., Homan, P., Jahanshad, N., Janssen, J., Ji, E., Kaiser, S., Kaleda, V., Kim, M., Kim, W-S., Kirschner, M., Kochunov, P., Kwak, Y. B., Kwon, J. S., Lebedeva, I., Liu, J., Mitchie, P., Michielse, S., Mothersill, D., Mowry, B., Ortiz-García de la Foz, V., Pantelis, C., Pergola, G., Piras, F., Pomarol-Clotet, E., Preda, A., Quidé, Y., Rasser, P. E., Rootes-Murdy, K., Salvador, R., Sangiuliano, M., Sarró, S., Schall, U., Schmidt, A., Scott, R. J., Selvaggi, P., Sim, K., Skoch, A., Spalletta, G., Spaniel, F., Thomopoulos, S. I., Tomecek, D., Tomyshev, A. S., Tordesillas-Gutiérrez, D., van Amelsvoort, T., Vázquez-Bourgon, J., Vecchio, D., Voineskos, A., Weickert, C. S., Weickert, T., Thompson, P. M., Schmaal, L., van Erp, T. G. M., Turner, J., Cole, J. H., Dima, D. ORCID: 0000-0002-2598-0952, Walton, E. & ENIGMA Schizophrenia Consortium (2022). Brain ageing in schizophrenia: evidence from 26 international cohorts via the ENIGMA Schizophrenia consortium. Molecular Psychiatry, 28(3), pp. 1201-1209. doi: 10.1038/s41380-022-01897-w


Schizophrenia (SZ) is associated with an increased risk of life-long cognitive impairments, age-related chronic disease, and premature mortality. We investigated evidence for advanced brain ageing in adult SZ patients, and whether this was associated with clinical characteristics in a prospective meta-analytic study conducted by the ENIGMA Schizophrenia Working Group. The study included data from 26 cohorts worldwide, with a total of 2803 SZ patients (mean age 34.2 years; range 18-72 years; 67% male) and 2598 healthy controls (mean age 33.8 years, range 18-73 years, 55% male). Brain-predicted age was individually estimated using a model trained on independent data based on 68 measures of cortical thickness and surface area, 7 subcortical volumes, lateral ventricular volumes and total intracranial volume, all derived from T1-weighted brain magnetic resonance imaging (MRI) scans. Deviations from a healthy brain ageing trajectory were assessed by the difference between brain-predicted age and chronological age (brain-predicted age difference [brain-PAD]). On average, SZ patients showed a higher brain-PAD of +3.55 years (95% CI: 2.91, 4.19; I2 = 57.53%) compared to controls, after adjusting for age, sex and site (Cohen's d = 0.48). Among SZ patients, brain-PAD was not associated with specific clinical characteristics (age of onset, duration of illness, symptom severity, or antipsychotic use and dose). This large-scale collaborative study suggests advanced structural brain ageing in SZ. Longitudinal studies of SZ and a range of mental and somatic health outcomes will help to further evaluate the clinical implications of increased brain-PAD and its ability to be influenced by interventions.

Publication Type: Article
Additional Information: This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit
Publisher Keywords: Neuroscience, Schizophrenia
Subjects: B Philosophy. Psychology. Religion > BF Psychology
Q Science > QH Natural history > QH301 Biology
R Medicine > RA Public aspects of medicine > RA0421 Public health. Hygiene. Preventive Medicine
Departments: School of Health & Psychological Sciences > Psychology
SWORD Depositor:
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