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

Summary Objective The pathophysiology of psychosis remains unclear. Preclinical, postmortem, and imaging evidence implicates iron and neuromelanin, but the consistency and magnitude of effects are uncertain. We aimed to characterise 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. Methods We 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. We 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 relaxation rate (R2*), and quantitative susceptibility mapping (QSM). Results Twenty-seven reports, including 879 individuals with psychosis and 813 controls, were analysed. Meta-analyses were conducted across the caudate nucleus, putamen, globus pallidus, thalamus, and substantia nigra. In psychosis, R2* was significantly lower across all examined regions (g= –0.27 to –0.40), QSM values were lower in the substantia nigra (g= – 0.61; 95% CI, –0.84 to –0.38), and R2 was lower in the caudate nucleus (g= –0.30; 95% CI, – 0.56 to –0.04). NM-MRI values in the substantia nigra were significantly higher (g= 0.39; 95% CI, 0.23 to 0.55), though this effect strongly correlated with chlorpromazine daily equivalent dose (β= 0.001; 95% CI, 0.0003 to 0.0018), suggesting medication-related effects. Conclusions Psychosis is associated with lower subcortical iron-sensitive MRI values. This was most marked in the substantia nigra, where NM-MRI values—which index neuromelanin-bound iron in dopamine neurones—were significantly higher. This suggests that while subcortical iron is overall lower in psychosis, neuromelanin-bound iron is increased within dopamine neurones. Investigating the mechanisms underlying iron alterations may provide new treatment targets.