¹Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Department of Psychiatry, Melbourne, Australia, ²Melbourne Neuropsychiatry Centre, Department of Psychiatry, The University of Melbourne, Department of Psychiatry, Melbourne, Australia, ³The Cooperative Research Centre (CRC), Mental Health, Victoria, Australia

Background: Brain imaging and QSM studies of schizophrenia have revealed significant structural and synaptic changes in the frontal and temporal regions. Emerging evidence suggests that schizophrenia, particularly treatment-resistant schizophrenia (TRS), may also involve neuroprogressive and neurodegenerative processes. These changes, including accelerated cortical thinning and frontotemporal abnormalities, resemble those seen in frontotemporal dementia (FTD), a neurodegenerative disorder with overlapping cognitive and psychiatric features. Although the underlying mechanisms for these morphological brain changes remain unclear, iron has been implicated due to its role in oxidative stress, neuroinflammation, and neuronal injury. While brain iron dysregulation has been studied, less attention has been given to peripheral iron-related proteins as potential biomarkers of disrupted brain iron homeostasis.

Aims & Objectives: This study aims to compare iron and iron-related protein levels in TRS and FTD patients to explore potential overlaps in iron homeostasis.

Method: We analyzed the iron levels in serum samples from TRS, FTD, and age-matched control groups by ICP-MS. Key iron-related proteins, such as Ferritin, Ferroportin-1, Transferrin, and Transferrin receptor, were evaluated using Western blot. The relationship between iron, protein levels and age were assessed using Graph Prism and SPSS software.

Results: TRS patients exhibited significantly lower serum iron levels than the FTD and control groups. No significant differences were found between the TRS, FTD and control groups in the Ferritin, Ferroportin-1, Transferrin, and Transferrin receptor levels. Iron levels in the TRS cohort showed an early age decline compared with controls; in contrast, FTD cases did not show a different pattern related to control individuals. In addition, in the TRS cohort, Ferroportin-1 levels significantly declined with age compared to age-matched controls, suggesting that Ferroportin-1 dysregulation may be more pronounced with increasing age in TRS. In contrast, the FTD group did not show differences from the control group. Finally, the Iron /Transferrin ratio significantly decreased in TRS but not in the FTD group.

Discussion & Conclusions: Collectively, our results indicate that TRS individuals display a disruption in key parameters that are involved in systemic iron homeostasis which are not observed in FTD cases. Therefore, the serum iron abnormality in TRS does not overlap with FTD.