Abstract
The limited efficacy of antidepressants for major depressive disorder (MDD) underscores the urgent need to explore mechanisms behind treatment heterogeneity and identify new antidepressant targets. This study explores the role of metabotropic glutamate receptor 5 (mGluR5) in MDD, examining mGluR5 availability changes pre- and post-treatment, and their link to clinical outcomes. We studied 25 patients with MDD and 21 healthy controls, with 13 undergoing eight-week vortioxetine treatment (10 mg per day). mGluR5 availability was measured at baseline and follow-up using [18F]3-fluoro-5-[(pyridin-3-yl)ethynyl]benzonitrile positron emission tomography ([18F]FPEB PET) scans, and patients were categorized on the basis of their response. Results showed lower mGluR5 availability in patients with MDD versus the control group at baseline. Post-treatment, the group with MDD exhibited significant increases in mGluR5 availability in the dorsolateral prefrontal cortex and ventromedial prefrontal cortex (N = 13, Cohen’s d = 0.83 and 1.01). The percentage increase in mGluR5 availability correlated with the percentage reduction in scores on the Hamilton rating scale for depression. These findings underscore mGluR5’s key role in MDD pathophysiology and treatment.
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Data availability
These are individual participant data from clinical trials, which cannot be publicly shared due to ethical and consent restrictions. Data access requests can be directed to the corresponding author ([email protected]). Requests will be reviewed on a case-by-case basis, and access may require submission of a research proposal and approval by an ethics committee. Responses to requests will be provided within 30 days.
Code availability
The code for the analysis performed in this study is available at https://github.com/AoqianDeng/mGluR5-Availability.
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Acknowledgements
This work was supported by the STI2030-Major Projects (grant no. 2021ZD0202000 to Y.Z.), the National Natural Science Foundation of China projects (grant no. 81671353 to Y.Z.), a major grant of the Key Research and Development Program of Hunan Province of China (grant nos. 2019SK2252 and 2022SK2035 to Y.Z.), and the Fundamental Research Funds for the Central Universities of Central South University (grant no. 2022ZZTS0856 to Y.Z.). We are grateful to C. Sun from the Shaanxi Brain Modulation and Scientific Research Center (Xi’an, Shaanxi, P. R. China), and S. Qi and Z. Huang from Xi’an Jiaotong University, for their assistance with image processing.
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B.L. was responsible for clinical study design, patient recruitment and follow-up coordination. A.D. contributed to study design, clinical data interpretation and drafting the manuscript. C.D. handled PET imaging data acquisition, preprocessing and quality control, and participated in the PET experimental design. W.C., Q.Z., W.O. and M.M. conducted patient recruitment, supported clinical assessments and optimized the study workflow. L.Z., F.H. and X.X. provided technical guidance on PET imaging methodology and assisted in data interpretation. J.L. and X.W. supervised clinical operations and workflow optimization. Y.W. and X.M. provided critical guidance on PET imaging study design and technical methodologies. H.H. offered expert advice on PET tracer applications and neuroimaging data interpretation. Y.J. and Y.Z. conceptualized the project, secured funding and supervised all aspects of the study.
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Liu, B., Deng, A., Dong, C. et al. Enhanced mGluR5 availability marks the antidepressant efficacy in major depressive disorder: an [18F]FPEB PET study. Nat. Mental Health 3, 298–305 (2025). https://doi.org/10.1038/s44220-025-00386-7
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DOI: https://doi.org/10.1038/s44220-025-00386-7
