Iron dysregulation across the schizophrenia lifespan: A systematic review from prenatal risk to postmortem findings

Iron plays a central role in neurodevelopment and dopaminergic regulation, yet its relationship with schizophrenia remains conceptually unresolved. Research conducted across the life span, from prenatal exposure to postmortem brain tissue, has produced fragmented findings without an integrating physiological framework. We aimed to systematically synthesize this literature and reinterpret prior findings through core principles of iron regulation, with particular attention to the distinction between absolute iron depletion and inflammation-driven functional restriction. We conducted a PROSPERO-registered systematic review (CRD42022382842) following PRISMA guidelines and included 51 studies spanning genetic risk, gestational exposure, peripheral biomarkers, neuroimaging, and postmortem analyses. Genetic studies do not implicate core iron-regulatory pathways in inherited schizophrenia risk. Large population-based cohorts consistently associate maternal iron deficiency during pregnancy with increased schizophrenia risk in offspring. Sixteen studies assessed adult peripheral iron markers; most report lower serum iron, although heterogeneity remains substantial. Few investigations evaluated regulatory markers such as hepcidin, and only one examined the hepcidin-ferroportin pathway directly. Neuroimaging studies in early psychosis report reduced subcortical iron alongside increased dopaminergic activity, whereas postmortem investigations describe cortical iron-ferritin decoupling in chronic stages. Across levels of analysis, apparent inconsistencies converge when iron physiology is considered. Absolute iron depletion and inflammation-driven functional iron restriction represent biologically distinct states that share reduced circulating iron but arise from different mechanisms. Stratifying schizophrenia according to iron phenotype offers a coherent framework to reinterpret prior evidence and guide future mechanistic research.