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Is treatment-resistant schizophrenia a neuroimmune condition? Meta-analytic evidence from magnetic resonance spectroscopy

Neuropsychopharmacology volume 50, pages 341–342 (2025)Cite this article

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A Correction to this article was published on 19 March 2025

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Although the advent of next-generation antipsychotics has proven invaluable in treating schizophrenia (SZ), up to 33% of individuals with SZ do not show symptomatic improvement with first-line treatments [1]. Clozapine is then prescribed for these patients, for whom non-response rates of up to ~60% may still be observed [1]. Failing these conventional forms of treatment, alternatives are then prescribed (e.g., electroconvulsive therapy), with limited clinical response a common outcome [2].

As the primary mechanism of antipsychotic action is mediated via dopaminergic receptors, it is hypothesized that treatment-resistant SZ (TRSZ) is associated with a non-dopaminergic pathology. The nature of this pathology, however, is unclear. Possible mechanisms include variations in dopaminergic sensitivity, glutamatergic signaling, and oxidative stress [3]. Another possibility is that TRSZ is associated with a neuroimmune phenotype, as the association of maternal infections (with associated immune response) with psychosis risk, genetic associations with immune related genes, and increased cytokine levels and brain free water measures in psychosis have suggested that neuroimmune mechanisms may contribute to SZ pathophysiology [4]. Furthermore, the only effective treatment for some patients with TRSZ is clozapine, which may anti-inflammatory properties in vitro [5].

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Fig. 1: Top: Meta-analysis forest plot for 6 datasets reporting anterior cingulate cortex (ACC) total choline in treatment-resistant schizophrenia (TRSZ) vs. non-TRSZ.

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References

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Acknowledgements

The authors thank Richard J. Maddock, M.D., for assistance with the manuscript.

Funding

This work was supported by the National Institutes of Mental Health (C.S.C., grant numbers MH059883, MH122139, MH106438, J.S., grant number MH125096).

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  1. Department of Psychiatry, University of California, Davis, CA, USA

    Jason Smucny

  2. Department of Psychiatry, University of California, Irvine, CA, USA

    Cameron S. Carter

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  1. Jason Smucny
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JS and CSC wrote the manuscript.

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Correspondence to Jason Smucny.

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Smucny, J., Carter, C.S. Is treatment-resistant schizophrenia a neuroimmune condition? Meta-analytic evidence from magnetic resonance spectroscopy. Neuropsychopharmacol. 50, 341–342 (2025). https://doi.org/10.1038/s41386-024-01932-0

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