Associations of Neuromelanin in the Substantia Nigra with Antipsychotic Response in Schizophrenia

Approximately 30% of patients with schizophrenia do not respond to antipsychotics. While schizophrenia has been primarily explained by the dopamine dysfunction hypothesis, treatment-resistant schizophrenia (TRS) may involve a different pathophysiology. Neuromelanin (NM), a product of dopamine metabolism in the substantia nigra (SN), indirectly measures long-term dopamine synthesis capacity. Few studies have examined SN NM levels in TRS. Therefore, we investigated the relationship between SN NM levels and treatment responsiveness in schizophrenia. We included age- and sex-matched TRS, patients with schizophrenia in remission of positive symptoms (SZ-R), and healthy controls (HCs). Neuromelanin-sensitive magnetic resonance imaging was used to measure SN NM signals. We also evaluated clinical symptoms and cognitive impairment. We conducted voxel-wise analyses of NM contrast-to-noise ratio (CNR) to compare groups pairwise. Correlation analyses examined relationships between NM signals and symptom severity. Seventy-two participants (n = 24 per group) completed the study. The TRS group had higher dorsal SN CNR than the HC group (510 out of 1948 voxels at p < 0.05, corrected p = 0.005, permutation test). In contrast, no significant differences were observed in the other comparisons. No significant correlations were found between NM CNR and clinical severity. Our findings contrast with previous positron emission tomography studies on dorsal striatal dopamine function. Since the dorsal SN contributes to both the mesolimbic and nigrostriatal pathways, with a relatively greater role in the former, dopamine functions in these pathways may play different roles for treatment responsiveness. Further research with multimodal imaging is needed to examine dopamine function and antipsychotic treatment responsiveness in schizophrenia.