Background: Clinical forecasting models have potential to optimize treatment and improve outcomes in psychosis, but predicting long-term outcomes is challenging and long-term follow up data are scarce. In this 10-year longitudinal study we aimed to characterize the temporal evolution of cortical correlates of psychosis and their associations with symptoms. Design: Structural MRI from people with first-episode psychosis and controls (n=79 and 218) were obtained at enrollment, after 12 months (n=67 and 197), and 10 years (n=23 and 77), within the Thematically Organized Psychosis (TOP) study. Normative models for cortical thickness estimated on public MRI datasets (n=42983) were applied to TOP data to obtain deviation scores for each region and timepoint. Positive And Negative Syndrome Scale (PANSS) scores were acquired at each timepoint along with registry data. Linear mixed effects (LME) models assessed effects of diagnosis, time and their interactions on cortical deviations plus associations with symptoms. Results: LMEs revealed main effects of diagnosis and time x diagnosis interactions in a distributed cortical network, where negative deviations in patients attenuate over time. In patients, symptoms also attenuate over time. LMEs revealed effects of anterior cingulate on PANSS total scores, and insular and orbitofrontal regions on PANSS negative scores. Conclusions: This long-term longitudinal study revealed a distributed pattern of cortical differences which attenuated over time together with a reduction in symptoms. These findings are not in line with a simple neurodegenerative account of schizophrenia, and deviations from normative models offer a promising avenue to develop biomarkers to track clinical trajectories over time.

OAA Consultant to cortechs.ai, speaker honorarium from Sunvion, Janssen, Lundbeck. Regional PI for clinical trials funded by BI, MAPS, Janssen. Other authors do not report any conflict of interests.

This study was supported by grant number BRAINCHART, 215698/Z/19/Z from the Wellcome Trust Innovator Award, the Research Council of Norway (#223273, #287714), the KG Jebsen Stiftelsen, the European Research Council under the European Union Horizon 2020 Research and Innovation program (ERC StG, grant 802998), and South-Eastern Norway Regional Health Authority (grants #2006233, #2006258, #2009037, #2011085, #2011096, #2012100, #2014102, #2015088, #2018093, #2019107, #2020086).

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This study is approved by the Regional Ethics Committee of South-Eastern Norway. All participants gave informed consent by signing a written consent form. Consent could be withdrawn at any time.

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