¹Centre for Addiction and Mental Health, Brain Health Imaging Centre, Toronto, Canada, ²University of Toronto, Department of Psychiatry, Toronto, Canada, ³University of Yamanashi Faculty of Medicine, Department of Neuropsychiatry, Yamanashi, Japan, ⁴Renaissance School of Medicine, Stony Brook University, Department of Psychiatry and Behavioral Health, New York, United States, ⁵Keio University School of Medicine, Department of Neuropsychiatry, Tokyo, Japan, ⁶Columbia University, Department of Psychiatry, New York, United States, ⁷New York State Psychiatric Institute, Division of Translational Imaging, New York, United States, ⁸University of Toronto, Institute of Medical Science, Toronto, Canada, ⁹Centre for Addiction and Mental Health, Campbell Family Menta Health Research Institute, Toronto, Canada

Background: Neuromelanin (NM), a byproduct of monoamine metabolism, reflects dopamine and norepinephrine activity in the brain. NM-sensitive MRI sequences enable in vivo quantification of NM levels in the substantia nigra (SN) and locus coeruleus (LC), which correspond to dopamine and norepinephrine neuron activity, respectively. Striatal dopamine dysfunction is a hallmark of schizophrenia: increased striatal dopamine synthesis has been associated with responsiveness to first-line antipsychotics (first-line responders [FLR]), whereas normal striatal dopamine synthesis characterizes treatment-resistant schizophrenia (TRS). Clozapine is the only approved treatment for TRS; however, its relationship with NM-MRI-derived dopamine markers remains unexplored. Additionally, norepinephrine dysregulation, originating in the LC, has been implicated in delusions and cognitive impairments in schizophrenia, yet its role in treatment response remains unvalidated using NM-MRI.

Aims & Objectives: This study aims to elucidate the relationship between NM accumulation and treatment responsiveness in schizophrenia. Specifically, we sought to:

1. Compare NM-MRI-derived signal intensities in the SN and LC among schizophrenia subgroups and healthy controls (HCs).
2. Investigate differences in NM-related dopaminergic and noradrenergic activity between clozapine-nonresponsive TRS (ultra-resistant schizophrenia [URS]) and clozapine-responsive TRS (non-URS).
3. Explore associations between NM-MRI findings and clinical characteristics, including symptom severity and treatment outcomes.

Method: We conducted a cross-sectional study involving four groups: URS (n = 16), non-URS (n = 16), FLR (n = 20), and HCs (n = 26). NM-MRI was used to measure NM signals in the SN and LC, quantified as contrast ratios (CR). Group comparisons were performed, controlling for age and sex, with Benjamini–Hochberg correction applied for multiple comparisons. Associations between CR and clinical characteristics were also analyzed.

Results: Of the 78 participants, two (1 URS, 1 FLR) were excluded due to insufficient data quality. Significant group differences were observed in CR for both the SN and LC (SN: F(3,70) = 4.45, η² = 0.16, p = 0.01; LC: F(3,70) = 2.87, η² = 0.11, p = 0.04). In the SN, both URS (Cohen’s d = 1.01, p = 0.01) and FLR (Cohen’s d = 0.94, p = 0.01) showed elevated CR compared to HCs. In the LC, URS demonstrated higher CR than FLR (Cohen’s d = 0.99, p = 0.04). No significant associations were found between CR and clinical characteristics or symptom severity.

Discussion & Conclusions: This study highlighted distinct dopaminergic and noradrenergic activity patterns in schizophrenia subgroups. Elevated dopaminergic activity (SN CR) was observed in both URS and FLR, whereas heightened noradrenergic activity (LC CR) differentiated URS from FLR. These findings suggest NM-MRI’s potential in predicting treatment response in schizophrenia, underscoring the need for longitudinal studies to establish its clinical utility.