690. SERUM ELEMENTS AND OXIDATIVE STRESS INDICES ARE ALTERED IN TREATMENT-RESISTANT SCHIZOPHRENIA

Abstract Background The molecular basis of schizophrenia (Sz) is explained by genetics and environmental factors. Around 30% of individuals with Sz have chronic illness and are often treatment-resistant (TRS). Our postmortem and MRI studies identified disturbances in brain iron in cortical and subcortical regions of individuals with chronic Sz. These changes may reflect elevated oxidative stress that may promote brain changes in the disorder. However, there are no consistent reports of changes in serum levels of elements in Sz. Aims & Objectives The main aim of this work was to examine serum levels of elements and indices of oxidative stress in a cohort of TRS compared to control individuals. We assessed the effect of age and serum Clozapine levels on these elements and assessed levels of proteins, GPX3 antioxidant activity, total serum antioxidant capacity, pro-inflammatory cytokines TNF-α and IL-6, and haematological parameters. Method Individuals with TRS (N=70) and matched controls (N=53) were recruited from clinics in North-Western Melbourne. Complete hematologic analyses were performed on blood samples. Metals and trace elements were determined by ICP-MS; proteins assessed by Western blot; GPX3 activity by NADPH oxidation assay; and total Antioxidant Capacity (AOX) by a Radical Trapping Antioxidant Assay. Determination of IL-6 and TNF-α was assessed by a multi-Plex ELISA assay. Statistical analyses were performed using GraphPad Prism 11 and IBM SPSS 29 software. Results Serum iron and selenium are significantly decreased in TRS individuals compared to controls. In addition, the TRS group showed elevated levels of pro-inflammatory cytokines and hepcidin and low GPX3 activity, which are involved in the antioxidant response. However, AOX was significantly increased in TRS compared to controls. The changes in serum elements were not affected by age, gender, or Clozapine dose. Discussion & Conclusions The decrease in selenium may explain the reduction in GPX3 activity and the elevation in pro-inflammatory cytokines, which in turn would trigger hepcidin secretion. High levels of hepcidin promote the degradation of Ferroportin-1 and the decrease in serum iron, which is in line with our findings. Importantly, the increase of AOX in the TRS group may be part of a compensatory response against the decrease in GPX3 activity.