A better mechanistic understanding of schizophrenia spectrum disorders is crucial to developing efficient treatment approaches. Therefore, this study investigated longitudinal interrelations between clinical outcomes, brain structure, and somatic health in post-acute individuals from the schizophrenia spectrum.

A sample of 63 post-acute patients from two independent physical exercise studies was included in the final analyses. Demographic, clinical, cognitive, and somatic data were acquired at baseline and follow-up, as were structural magnetic resonance imaging scans. Multivariate cross-lagged panel modeling including mediators was used to study the mutual interrelations over time between the clinical, neural, and somatic levels.

A higher baseline global gray matter volume and larger regional gray matter volumes of the hippocampal formation, precuneus, and posterior cingulate predicted improved clinical outcomes, such as daily-life functioning, negative symptoms, and cognition. Increases in white matter volume from baseline to follow-up resulted in significantly reduced positive symptoms and higher daily-life functioning.

Our findings suggest that stimulating neuroplasticity, especially in the hippocampal formation, precuneus, and posterior cingulate gyrus, may represent a promising treatment target in post-acute schizophrenia spectrum disorders. Physical exercise therapies and other lifestyle interventions, and brain stimulation approaches reflect potential treatment candidates. Given the exploratory character of the statistical analysis performed, these findings need to be replicated in independent longitudinal imaging cohorts of patients with schizophrenia spectrum disorders.