Peripheral and central innate immune alterations in schizophrenia and bipolar disorder: a systematic review of NK cells, monocytes and macrophages

Background: Innate immune dysfunction is implicated in schizophrenia (SZ) and bipolar disorder (BD). Alterations in natural killer (NK) cells, monocytes and macrophages occur in both disorders across peripheral and central compartments. This systematic review synthesises current evidence by clinical stage and illness phase. Methods: Following PRISMA guidelines, PubMed, Scopus and PsycINFO were searched to May 2025. Eligible studies reported peripheral blood, cerebrospinal fluid (CSF) or post-mortem brain findings. Findings: Eighty-one studies met inclusion criteria. In SZ, peripheral data showed altered NK cell subsets and monocyte abnormalities, including elevated counts and inflammatory ratios, particularly in early or acute stages. CSF studies found increased monocyte chemoattractants, and post-mortem analyses revealed macrophage upregulation in frontal and temporal cortices. In BD, NK cell results were limited and inconsistent. Monocyte activation was most evident during symptomatic phases, particularly mania. CSF analyses detected increased monocyte- and macrophage-associated proteins, while post-mortem findings indicated microglial activation in selected cortical and subcortical regions, less consistently than in SZ. Interpretation: Innate immune alterations in SZ and BD partly overlap yet remain disorder- and state-specific. Central compartments and NK cells are underexplored. Stratification by stage and phase may improve interpretability and guide longitudinal, multimodal, cell-specific research for precision immunopsychiatry.