Abstract
Major depressive disorder (MDD) is a highly heterogeneous mental illness, marked by clinical variability and distinct neuropathological mechanisms. This study sought to enhance diagnostic precision for MDD by identifying neurophenotypes using a normative model of regional homogeneity (ReHo), offering new avenues for precision medicine. Using resting-state functional magnetic resonance imaging data from 1101 patients with MDD and 1011 healthy controls (HCs) sourced from the REST-meta-MDD project, we developed the first normative model of ReHo. Gaussian process regression was applied to predict a normative lifespan trajectory based on age and sex in HCs, enabling quantification of individual deviations from the model for patients with MDD. Unsupervised clustering algorithms were then employed to classify MDD subtypes, followed by validation analyses to assess clustering stability. Significant deviations from the normative ReHo model were observed in patients with MDD. Two distinct MDD subtypes emerged: Emotional dysregulation subtype, characterized by negative deviations in the frontoparietal control network, ventral attention network, default mode network, and limbic network (Cohen’s d = 0.40−1.75, FDR-corrected p < 0.05). This subtype correlated with more severe overall depressive symptom (d = 0.17, p = 0.010), better insight (d = −0.25, p = 0.009), younger age (d = −0.19, p = 0.003), lower medication usage (Cramer’s V = 0.09, p = 0.017), a negative correlation between symptom severity and illness duration (r = −0.21, p < 0.001), severe brain dysfunction (Partial η2 = 0.00–0.01, FDR-corrected p < 0.05), and higher neural vulnerability (positive: 0.25%–4.03%, d = 0.12, FDR-corrected p = 0.177; negative: 0.25%–2.01%, d = 0.31, FDR-corrected p < 0.05). Perceptual dysregulation subtype, defined by negative deviations in the sensorimotor network, visual network, and dorsal attention network (d = 0.52–1.81, FDR-corrected p < 0.05). This subtype was associated with more severe anxiety/somatization symptoms (d = −0.15, p = 0.031), older age, higher medication usage, poorer insight, and stable neural vulnerability (positive: 0.14%–2.98%, d = 0.08, FDR-corrected p = 0.333; negative: 0.14%–1.42%, d = −0.24, FDR-corrected p < 0.05). These neuroimaging distinctions corresponded to clinical differences between subtypes, illuminating the heterogeneity of MDD. The findings emphasize the necessity of personalized interventions tailored to the unique neuropathological mechanisms of each subtype, advancing precision medicine in MDD.
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The data that support the findings of this study are available from the corresponding author upon reasonable request.
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Acknowledgements
We would like to thank Professor Mingrui Xia and Dr. Xiaoyi Sun for their valuable assistance in preparing this manuscript. We also acknowledge the REST-meta-MDD Project from the DIRECT Consortium for providing access to their publicly available data, which significantly contributed to the success of this research. This work was supported by the National Natural Science Foundation of China (grant number 82471546, 82322024), Guangzhou Health Science and Technology Project (grant number 20251A010033), Innovative Clinical Technique of Guangzhou (2024-2026), Guangzhou Key Clinical Specialty (Clinical Medical Research Institute).
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LZJ was responsible for investigation, methodology, formal analysis, writing the original draft, and visualization. LWC, XYB, SJH, WCY, LXF, LGX, LZH, HZY, MSM, ZMQ, SXD, and LHN were responsible for investigation. ZYL contributed to validation, project administration, and investigation. NYP was responsible for conceptualization, supervision, and writing—review and editing.
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This study was approved by the Ethics Committee of 25 hospitals in the REST-meta-MDD Project from the DIRECT Consortium. All participants provided written informed consent.
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Luo, Z., Li, W., Xu, Y. et al. Identifying neurophenotypes of major depressive disorder through normative model of regional homogeneity. Transl Psychiatry (2026). https://doi.org/10.1038/s41398-026-04003-8
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DOI: https://doi.org/10.1038/s41398-026-04003-8
