EVALUATION OF NEUROMELANIN IN PATIENTS WITH TREATMENT- RESISTANT SCHIZOPHRENIA
Authors: Tarumi *Ryosuke , Honda Shiori , Etani Takahide , Homma Saki , Kaneko Yuka , Matsushita Karin , Moriyama Sotarou , Tobari Yui , Ueno Fumihiko , Horga Guillermo , Cassidy Clifford , Tsugawa Sakiko , Uchida Hiroyuki , Graffguerrero Ariel , Noda Yoshihiro , Nakajima Shinichiro 
Published: February 2025

Abstract

Background
Approximately 30% of patients with schizophrenia (SZ) do not respond to antipsychotic treatment. Although abnormalities of the dopamine (DA) function are implicated in the pathophysiology of SZ, reports on striatal DA function and treatment responsiveness are inconsistent.The striatum is modified by dopamine released from the substantia nigra (SN). Neuromelanin (NM) is a product of monoamine metabolism including DA. NM-sensitive MRI sequences allow in vivo quantification of NM levels in the SN. NM-MRI signal is thought to serve as a biomarker for SN DA neuron integrity, and in turn, striatal DA functioning. A recent meta-analysis (1) reported that NM levels were higher in patients with SZ than healthy controls (HCs), but no studies have reported on the relationship between NM levels and treatment responsiveness in this population.

Aims
The purpose of this study was to investigate the relationship between midbrain DA function and treatment responsiveness in patients with schizophrenia.

Methods
This study was approved by the Ethics Committee of Keio University School of Medicine and Komagino Hospital (approval numbers: 20170313, 20230003). We recruited patients with treatment- resistant schizophrenia (TRS) and patients with non-TRS from Komagino Hospital (Tokyo, Japan). We used a 3T GE MRI with a 8-channel head coil and applied NM sensitive MRI (2D GRE MT, TR=260ms) to measure NM signals in the SN. We also evaluated the severity of symptoms using the Positive and Negative Symptom Scale (PANSS). First, we conducted an analysis of covariance to compare the levels of NM signals between the TRS and non-TRS groups controlling for age and sex as covariates. Subsequently, we performed correlation analyses to explore relationships between severity of symptoms and NM signals.

Results
Forty-nine participants (TRS: n=17; non-TRS: n=21) completed the study. Overall group differences were found in contrast-to-noise ratio (CNR)-NM ((F(1, 34)=3.04, p=0.082, Adjusted R2=23.9%)). Specifically, the TRS group showed higher CNR-NM compared to the non-TRS group (p =0.03, Cohen’ s d=2.46). Correlations were not found between CNR-NM and age or between CNR-NM and PANSS scores in each group. In the whole patient group, CNR-NM was higher in women (t (36) = 2.5, p = 0.017) and associated with PANSS positive scores (r=0.45, p=0.005).

Conclusion
The present study demonstrated elevated SN DA function in TRS compared to non-TRS. PET studies have shown inconsistent relationships between treatment response and striatal DA function. Further research is needed to examine the relationship between antipsychotic treatment response and dopamine function in the nigrostriatal pathway of schizophrenia.

References
(1)Ueno, F. et al. (2022) 'Neuromelanin accumulation in patients with schizophrenia: A systematic review and meta-analysis,' Neuroscience &Biobehavioral Reviews, 132, pp. 1205–1213. https://doi.org/10.1016/j.neubiorev.2021.10.028.