Heterogeneity of schizophrenia through a peripheral inflammation lens: A mini-review

Schizophrenia is increasingly recognized as a heterogeneous disorder, and immune dysregulation may contribute to its variability. Recent evidence suggests biologically distinct inflammatory subtypes within schizophrenia. This review aims to identify inflammatory subgroups defined by peripheral inflammatory markers and examine whether these subgroups exhibit distinct biological or neuroimaging characteristics. To do this, we conducted a systematic search across PubMed, Web of Science, PsycINFO, and Scopus. Studies were included if they investigated the subgrouping of patients with schizophrenia based on peripheral inflammatory markers, including protein levels, gene expression, or immune-related epigenetic features. Twenty studies met the inclusion criteria, nine of which incorporated MRI to further characterize inflammation-related subgroups. Most studies employed data-driven clustering approaches to classify patients into high- and low-inflammation subtypes. High-inflammation subtypes were frequently associated with more severe symptoms, cognitive impairments, and pronounced brain structural changes. Although MRI modalities and outcomes varied, the literature suggests a potential association between inflammatory subtypes and structural or functional brain alterations. These findings emphasize the immunological heterogeneity of schizophrenia and support the potential of immunological stratification to uncover biologically meaningful subtypes, warranting further research into the underlying mechanisms and clinical applications.