Gray Matter Iron and Neuromelanin in Psychosis: A Systematic Review and Meta-Analysis of MRI Studies

The pathophysiology of psychosis remains unclear. Preclinical, postmortem, and imaging evidence implicates iron and neuromelanin abnormalities, but the consistency and magnitude of effects are uncertain. The authors characterized brain iron and neuromelanin alterations in psychosis through a systematic review and meta-analysis of iron-sensitive MRI and neuromelanin-sensitive MRI (NM-MRI) studies.

The authors searched Embase, PubMed, and PsycINFO from inception to October 31, 2025, for case-control studies using iron-sensitive MRI or NM-MRI in patients with psychosis. They used random-effects models to calculate effect sizes (Hedges' g) and meta-regressions to examine clinical confounders. The primary outcomes included effect sizes for NM-MRI and iron-sensitive MRI measures: transverse relaxation rate (R2), effective transverse relaxation rate (R2*), and quantitative susceptibility mapping (QSM).

Twenty-seven reports including 879 individuals with psychosis and 813 control subjects were analyzed. Meta-analyses were conducted across the caudate nucleus, putamen, globus pallidus, thalamus, and substantia nigra. Patients with psychosis showed significantly lower R2* across all examined regions (g values, -0.40 to -0.27), lower QSM values in the substantia nigra (g=-0.61, 95% CI=-0.84, -0.38), lower R2 in the caudate nucleus (g=-0.30, 95% CI=-0.56, -0.04), and higher NM-MRI values in the substantia nigra (g=0.39, 95% CI=0.23, 0.55). However, this effect was correlated with antipsychotic dosage (β=0.001, 95% CI=0.0003, 0.0018).

Psychosis is associated with lower subcortical iron-sensitive MRI values, most prominently in the substantia nigra, alongside higher nigral NM-MRI values, which index neuromelanin-bound iron in dopamine neurons. Antipsychotic exposure may contribute to higher NM-MRI values, but confounding by indication cannot be excluded, highlighting the need for longitudinal studies. These findings suggest that while subcortical iron is lower overall in psychosis, neuromelanin-bound iron is increased within dopamine neurons. Investigating the mechanisms underlying these iron alterations may provide new treatment targets.