Schizophrenia spectrum disorders (SSD) are associated with accelerated brain aging, reflected in an increased brain age gap. This gap serves as a biomarker, indicating poorer brain health, cognitive deficits, and greater severity in specific symptom domains. Physical exercise holds promise as an adjunct therapy to mitigate these deficits by potentially promoting brain recovery. However, the extent of overall improvements in brain health following exercise, along with their predictors and relationships to symptom clusters, are yet to be determined. This study examined the brain age gap metric as a quantitative indicator of brain recovery in response to physical exercise. To achieve this, we aggregated data from two randomized controlled trials, analyzing baseline (n = 134) and 3- or 6-month post-exercise (n = 46) data from individuals with SSD. Our findings revealed that patients with a higher baseline BMI demonstrated greater brain recovery, as evidenced by a reduced brain age gap post-exercise. Furthermore, changes in the brain age gap were associated with improvements in negative symptoms and cognition, suggesting that reductions in brain-predicted age may reflect symptom relief, particularly in domains beyond positive symptoms. These results underscore the importance of BMI in brain health, support using the brain age gap as a surrogate marker for tracking clinically relevant brain recovery, and highlight the need for stratified interventions and combined lifestyle modifications to enhance outcomes in SSD. Keywords: schizophrenia spectrum disorders, brain age gap, physical exercise, neuroplasticity, brain recovery, treatment response, polygenic risk

PF is a co-editor of the German (DGPPN) schizophrenia treatment guidelines and a co-author of the WFSBP schizophrenia treatment guidelines; he is on the advisory boards and receives speaker fees from Boehringer-Ingelheim, Janssen, Lundbeck, Otsuka, Servier, and Richter. JHC is a scientific advisor to and shareholder in Brain Key and Claritas HealthTech PTE. DY, AS, DK, BM, SP, IM, and LR declare no conflicts of interest or financial disclosures relevant to this research. There was no role of the sponsors in relation to the study design, collection, analysis and interpretation of data, writing of the report, and the decision to submit the article for publication.

NCT01776112, NCT03466112

https://osf.io/tr3nx/

The work was supported by the German Federal Ministry of Education and Research (BMBF) through the research network on psychiatric diseases ESPRIT (Enhancing Schizophrenia Prevention and Recovery through Innovative Treatments; coordinator: Andreas Meyer-Lindenberg; grant number, 01EE1407E) awarded to PF and AS. Furthermore, the study was supported by the Else Kroener-Fresenius Foundation with the Research College Translational Psychiatry for PF, AS, and IM (Residency/PhD track of the International Max Planck Research School for Translational Psychiatry [IMPRS-TP]), and Max Planck School of Cognition, Max Planck Institute for Human Cognitive and Brain Sciences, Leipzig, Germany, for DY. The study was endorsed by the Federal Ministry of Education and Research (Bundesministerium fuer Bildung und Forschung [BMBF]) within the initial phase of the German Center for Mental Health (DZPG) (grant: 01EE2303A, 01EE2303F to PF, AS).

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Ethics committee of Ludwig Maximilian University of Munich gave ethical approval for this work.

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