Morphological alterations of the thymus gland in individuals with schizophrenia

Despite its critical function in the immune system and accumulating evidence of immunological abnormalities in schizophrenia, the thymus has long been overlooked. We aimed to investigate thymic morphological alterations and their corresponding heterogeneity in patients with schizophrenia. Imaging-derived thymic morphology was assessed and compared between 419 patients with schizophrenia and 460 age- and sex-matched control participants aged 16-40 years who underwent chest computed tomography (CT) scanning. These included measurements reflecting thymic size and density, such as average maximal thickness, anteroposterior distance, and average CT attenuation, which were also used to identify patient subtypes based on an unsupervised machine learning algorithm. Once the thymus-based patient subtypes were identified, between-subtype differences in the thymic and blood immunometabolic profiles were further tested. Case-control comparisons revealed that patients had greater average maximal thickness (Glass's delta [Δ] effect size = 0.37) but lower average CT attenuation (Δ = -0.18) in the thymus than controls. Two thymus-based subtypes with disparate thymic and blood immunometabolic profiles were identified. Specifically, Subtype 1 (containing 40.1% of patients) was characterized as greater average maximal thickness (Δ = 1.36) and longer anteroposterior distance (Δ = 0.71) but lower CT attenuation (Δ = -0.97), contrary to the abnormal patterns of Subtype 2. Furthermore, Subtype 1 had higher levels of blood immunometabolic profiles, such as lymphocyte count and lipid measures, than Subtype 2. Altered thymic morphology with considerable heterogeneity was first reported in schizophrenia, providing evidence for the immune hypothesis and facilitating the discovery of imaging biomarkers reflecting the immunometabolic status.