ASSOCIATIONS BETWEEN NEUROMELANIN ACCUMULATION IN PATIENTS WITH SCHIZOPHRENIA AND TREATMENT RESPONSIVENESS: A CROSS- SECTIONAL NM-MRI STUDY

Abstract Background Neuromelanin (NM) is a byproduct of monoamine metabolism, including that of dopamine. NM-sensitive Magnetic Resonance Imaging (NM-MRI) sequences enable the in vivo quantification of NM levels in the substantia nigra (SN). The NM-MRI signal is considered a surrogate marker for the integrity of SN dopamine neurons and, consequently, striatal dopaminergic functioning. Elevated striatal dopamine synthesis is associated with patients responsive to first-line antipsychotics (FLR) in schizophrenia, while normal striatal dopamine synthesis is implicated in the pathophysiology of treatment-resistant schizophrenia (TRS). Clozapine is the only antipsychotic currently approved for TRS. However, no studies have yet explored the relationship between SN accumulations, as measured by NM-MRI, and clozapine response in TRS patients. Aims & Objectives The study aims to investigate differences in dopaminergic activities among schizophrenia patients based on their treatment response, using NM-MRI. Methods The study enrolled TRS patients who either did not respond to clozapine (ultra-resistant schizophrenia [URS]) or did respond (non-URS), along with FLR patients and healthy controls (HCs). TRS was defined as resistance to at least two first-line antipsychotics and ongoing clozapine treatment at the time of the study. SN-NM levels were measured using 3T-MRI. The Contrast Ratio (CR) was calculated as the relative signal intensity difference between the SN and the crus cerebri. SN-CR values were compared between groups, controlling for age and sex. Associations between SN-CR and symptom severity scores were also explored within patient groups. Results A total of 78 participants (URS: n=16; non-URS: n=16; FLR: n=20; HCs: n=26) completed the study. Overall group differences in SN-CR values were significant (F(3,72)=3.80, η2=0.21, p=0.001). Specifically, URS patients (Cohen’ s d=0.86, p=0.049) and FLR patients (Cohen’ s d=1.27, p<0.0001) exhibited higher SN-CR values compared to HCs. No associations were found between SN-CR values and symptom severity scores within each group or the entire patient cohort. Discussion & Conclusion This study is the first to assess a proxy measure of mesostriatal dopamine function in schizophrenia patients, stratified by treatment responsiveness, using NM-MRI. We observed elevated SN-NM contrast in URS and FLR patients compared to HCs, and levels similar to HCs in non-URS patients. Longitudinal studies are warranted to determine whether SN-NM levels can serve as a reliable biomarker for predicting treatment response in schizophrenia.