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Distinct structural deficits in treatment-resistant schizophrenia and their putative neurotransmitter basis: a source-based morphometry analysis

Neuropsychopharmacology (2025)Cite this article

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Abstract

Schizophrenia is associated with widespread gray matter reduction. This is influenced by the underlying connectivity, resulting in covarying patterns of structural changes that are more pronounced in treatment-resistant individuals. However, it remains uncertain whether a distinct network of brain regions, with specific neurotransmitter basis, forms the substrate for treatment resistance in schizophrenia. We investigated the structural covariance networks (SCN) in 198 individuals; 55 with treatment-resistant schizophrenia (TRS) and 79 without TRS (non-TRS) in active symptomatic phase, and 64 healthy controls (HC) using Calhoun’s Source-Based Morphometry. We mapped the putative neurotransmitter basis of the SCNs using a PET-based chemoarchitectural atlas. Twelve independent components (i.e., SCNs) were identified. A prefrontal-limbic SCN had lower gray matter volume (GMV) in TRS compared to HC and non-TRS (F = 7.757, p < 0.001, FDR-corrected). Spatial correlation with chemoarchitectural atlas revealed predominant contributions from serotonergic [5HT1b and 5HT2a], glutamatergic [mGluR5], histaminergic [H3], and opioid [MOR] receptors for this TRS-related SCN (all pspin-permutation < 0.05, FDR-corrected). A different SCN comprised of dorsal fronto-temporal and parieto-occipital regions, not associated with  any specific neurotransmitter distribution, exhibited reduced GMV in both TRS and non-TRS groups vs. HC (F = 7.239, p < 0.001, FDR-corrected). Amidst the generic GMV reduction that is shared with non-TRS patients, patients with TRS have specific prefrontal-limbic structural deficits with a unique non-dopaminergic chemoarchitecture. These findings indicate a putative molecular and structural basis for poor treatment response, guiding the development of second- and third-line pharmacotherapies for TRS.

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Fig. 1: Spatial distribution and functional annotation of the two structural covariance networks (IC08 and IC10).
Fig. 2: Functional network contribution to the two structural covariance networks (IC08 and IC10).
Fig. 3: Post-hoc group comparisons of IC08 and IC10 loading coefficients.
Fig. 4: Spatial Spearman correlations between IC and neurotransmitter maps.

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Data availability

The datasets generated and/or analyzed during the current study are not publicly available due that they contain patients’ personal information, and our hospital has strict data sharing policy, but are available from the corresponding author on reasonable request.

Code availability

The accompanying code for this study is available on GitHub (https://github.com/huanhuang1988/TRS_neuromaps).

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Acknowledgements

The authors would like to express their sincere gratitude to all subjects for their time and efforts.

Funding

The study is supported by the Fundamental Research Funds for the Central Universities (2042020kf0128), Health Commission of Hubei Province scientific research project (WJ2021M142), the Medical Science Advancement Program of Wuhan University (TFLC2018001), Interdisciplinary Innovative Talents Foundation from Renmin Hospital of Wuhan University (JCRCFZ-2022-003), Hubei Provincial Science and Technology Plan Project (2023BCB133), and National Natural Science Foundation of China (82471523). L. Palaniyappan’s research is supported by the Canada First Research Excellence Fund, awarded to the Healthy Brains, Healthy Lives initiative at McGill University (through a New Investigator Supplement to LP) and Monique H. Bourgeois Chair in Developmental Disorders and the Graham Boeckh Foundation. He receives a salary award from the Fonds de recherche du Québec-Santé (FRQS 366934).This work was undertaken with the support of a China Canada High Level Medical Research Talent Fellowship for HH supervised by LP.

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Authors and Affiliations

  1. Department of Psychiatry, Renmin Hospital of Wuhan University, Wuhan, China

    Huan Huang, Xiaowei Wang, Xuan Qin, Rui Xu, Ying Xiong, Cheng Chen, Qirong Wan, Hao Liu, Chang Shu & Huiling Wang

  2. Douglas Mental Health University Institute, Department of Psychiatry, McGill University, Montreal, QC, Canada

    Huan Huang & Lena Palaniyappan

  3. Department of Psychiatry, Yidu People’s Hospital, Yidu, China

    Wei Yuan & Yunlong Peng

  4. Institute of Psychology, Chinese Academy of Sciences, Beijing, China

    Yuan Zhou

  5. Hubei Provincial Key Laboratory of Developmentally Originated Disease, Wuhan, China

    Huiling Wang

  6. Department of Psychiatry, Schulich School of Medicine and Dentistry, Western University, London, ON, Canada

    Lena Palaniyappan

  7. Robarts Research Institute, Schulich School of Medicine and Dentistry, Western University, London, ON, Canada

    Lena Palaniyappan

Authors
  1. Huan Huang
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  2. Xiaowei Wang
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  3. Xuan Qin
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  4. Rui Xu
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  10. Wei Yuan
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  11. Yunlong Peng
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  12. Yuan Zhou
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  13. Huiling Wang
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  14. Lena Palaniyappan
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Contributions

HLW and LP designed the study. HH, WXW, XQ, RX, YX, CC, WY, YLP, HL, QRW, and HLW conducted subjects’ recruitment and performed the study. HH, LP, YZ, WXW, and XQ undertook the data analysis; HH wrote the first draft of the manuscript. WHL and LP revised the manuscript. All authors contributed to and have approved the final manuscript.

Corresponding authors

Correspondence to Huiling Wang or Lena Palaniyappan.

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Competing interests

The authors declare no competing interests.

Ethics

The authors confirm that all experiments involving human participants were performed in accordance with relevant guidelines and regulations. The Ethics Committee of Renmin Hospital of Wuhan University approved the study protocol. The written, informed consent of all subjects was obtained after receiving a complete description of the study.

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Huang, H., Wang, X., Qin, X. et al. Distinct structural deficits in treatment-resistant schizophrenia and their putative neurotransmitter basis: a source-based morphometry analysis. Neuropsychopharmacol. (2025). https://doi.org/10.1038/s41386-025-02135-x

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