King's College London

Psychotic illnesses including schizophrenia and bipolar affective disorder are a leading cause of global disease burden. A significant proportion of people find current available treatments to be ineffective or intolerable. Understanding the brain’s pathophysiology – its functional, structural and biochemical changes – is a key part of translating psychosis research into new treatment options. Previous research has provided some evidence that there are abnormalities in iron and neuromelanin signals in the brain in psychotic illnesses, but the consistency and effects of this are uncertain.

New IoPPN-led research conducted a systematic review and meta-analysis of 27 reports, specifically looking at iron-sensitive MRI and neuromelanin-sensitive MRI (NM-MRI) research. The papers included 879 individuals with psychosis, and 813 control subjects.

Dr Vano continued, “Our meta-analysis of iron-sensitive MRI and NM-MRI studies robustly indicates that psychosis is associated with lower subcortical iron levels and nigral neuromelanin-iron accumulation relative to controls. Because neuromelanin renders iron biologically unavailable, elevated neuromelanin-bound iron alongside lower non-neuromelanin-bound iron in the substantia nigra may represent a compounded iron-deficient state. This could contribute to striatal hyperdopaminergia, making iron correction a potential dopamine-modifying treatment target.”

Analysis found a clear link between psychosis and a lower iron signal in subcortical regions of the brain, with this being most marked in the dopaminergic midbrain, the central nervous system’s hub of dopamine production. Signals were specifically found in the substantia nigra, a small part of the midbrain that controls body movement and emotional processing. The lower iron signal was most significant in patients experiencing first-episode psychosis, with a suggestion that the signal is higher in instances of chronic illness.

When looking at neuromelanin signals, researchers found it was greater in the dopaminergic midbrain for patients with psychosis compared with healthy controls. This effect strongly correlates with antipsychotic dose, which raises the possibility that antipsychotic use may be associated with neuromelanin accumulation.

The findings suggest that antipsychotic use may similarly increase neuromelanin signal in the substantia nigra. It is possible that antipsychotic treatment leads to greater dopaminergic activity, hence higher neuromelanin levels. Longitudinal studies assessing the effect of antipsychotic medication on NM-MRI are needed to resolve this uncertainty.

This paper also suggests that low iron levels in the substantia nigra are a feature of early-stage schizophrenia. Iron deficiency in the substantia nigra is associated with elevated dopamine activity in the striata. Given that elevated striatal dopamine is the critical neurotransmitter abnormality in schizophrenia and psychotic symptom severity, treating the lower nigral iron levels may modulate dopamine function, serving as a viable treatment target in schizophrenia.

In future, NM-MRI could be used to differentiate those with schizophrenia from healthy controls. Studies could therefore explore the biomarker potential of NM-MRI in different clinical syndromes, for example identifying treatment resistant schizophrenia at the time of onset, or those with an at-risk mental state who go on to develop schizophrenia. 

‘Gray Matter Iron and Neuromelanin in Psychosis: A Systematic Review and Meta-Analysis of MRI Studies’ by Vano, L.J. et al, was published in The American Journal of Psychiatry. https://doi.org/10.1176/appi.ajp.20251257