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Glutamatergic basis of antipsychotic response in first-episode psychosis: a dual voxel study of the anterior cingulate cortex

Neuropsychopharmacology volume 49, pages 845–853 (2024)Cite this article

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Abstract

A subgroup of patients with schizophrenia is believed to have aberrant excess of glutamate in the frontal cortex; this subgroup is thought to show poor response to first-line antipsychotic treatments that focus on dopamine blockade. If we can identify this subgroup early in the course of illness, we can reduce the repeated use of first-line antipsychotics and potentially stratify first-episode patients to intervene early with second-line treatments such as clozapine. The use of proton magnetic resonance spectroscopy (1H-MRS) to measure glutamate and Glx (glutamate plus glutamine) may provide a means for such a stratification. We must first establish if there is robust evidence linking elevations in anterior cingulate cortex (ACC) glutamate metabolites to poor response, and determine if the use of antipsychotics worsens the glutamatergic excess in eventual nonresponders. In this study, we estimated glutamate levels at baseline in 42 drug-naive patients with schizophrenia. We then treated them all with risperidone at a standard dose range of 2-6 mg/day and followed them up for 3 months to categorize their response status. We expected to see baseline “hyperglutamatergia” in nonresponders, and expected this to worsen over time at the follow-up. In line with our predictions, nonresponders had higher glutamate than responders, but patients as a group did not differ in glutamate and Glx from the healthy control (HC) group before treatment-onset (F1,79 = 3.20, p = 0.046, partial η2 = 0.075). Glutamatergic metabolites did not change significantly over time in both nonresponders and responders over the 3 months of antipsychotic exposure (F1,31 = 1.26, p = 0.270, partial η2 = 0.039). We conclude that the use of antipsychotics without prior knowledge of later response delays symptom relief in a subgroup of first-episode patients, but does not worsen the glutamatergic excess seen at the baseline. Given the current practice of nonstratified use of antipsychotics, longer-time follow-up MRS studies are required to see if improvement in symptoms accompanies a dynamic shift in glutamate profile.

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Fig. 1: Glutamate metabolite levels in the perigenual and dorsal Anterior Cingulate Cortex voxels at baseline in patients classified as Responders or Nonresponders at 12 weeks.
Fig. 2: Association between MRS glutamate metabolite signal in the dACC voxel, a node in the Salience Network at baseline and the degree of improvement in PANSS symptom domains from baseline to 12 weeks when taking risperidone.
Fig. 3: Glutamate metabolite levels in the dACC and pACC at baseline and 12 weeks in patients classified as Responders or nonresponders at 12 weeks.

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Funding

Funding

This work was supported by National Key Research and development plan of China (intergovernmental international scientific and technological innovation cooperation project, Grant No:2021YFE0191400), the National Natural Science Foundation of China (NSFC) (Grant No. 81871056 and 82101576), the Fundamental Research Funds for the Central Universities of Central South University (Grant No. 2020zzts287), Science and Technology Innovation Program of Hunan Province (Grant No. 2022RC1040 (ZL)) and China Scholarship Council (Grant No. 202106370192) for LF to train at the Douglas Research Centre. LP acknowledges research support towards this work from the Canada First Research Excellence Fund, awarded to the Healthy Brains, Healthy Lives initiative at McGill University (through New Investigator Supplement to LP); Monique H. Bourgeois Chair in Developmental Disorders and Graham Boeckh Foundation (Douglas Research Centre, McGill University) and a salary award from the Fonds de recherche du Quebec-Sante ́(FRQS).

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Authors and Affiliations

  1. Department of Psychiatry, National Clinical Research Center for Mental Disorders, and National Center for Mental Disorders, The Second Xiangya Hospital of Central South University, Changsha, China

    Lejia Fan, Yujue Wang, Xiaoqian Ma, Liu Yuan, Lijun Ouyang, Ying He, Zongchang Li & Xiaogang Chen

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

    Lejia Fan & Lena Palaniyappan

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

    Liangbing Liang & Lena Palaniyappan

  4. Department of Radiology, Hunan Children’s Hospital, Changsha, China

    Chunwang Li

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Contributions

XC: Supervision, Funding acquisition, Project administration. LP: Conceptualization, supervision of analysis, writing of original and revised drafts. LF: conceptualization, methodology, acquisition and analysis of data, writing of original and revised drafts. LL: conceptualization, revised drafts. Performed research (acquisition, analysis, and interpretation of data): YW, XM, LY, LO, YH, ZL, CL. All authors contributed to drafting and approved the final version of the manuscript.

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Correspondence to Xiaogang Chen or Lena Palaniyappan.

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LP reports personal fees for serving as chief editor from the Canadian Medical Association Journals, speaker/consultant fee from Janssen Canada and Otsuka Canada, SPMM Course Limited, UK, Canadian Psychiatric Association; book royalties from Oxford University Press; investigator-initiated educational grants from Janssen Canada, Sunovion and Otsuka Canada outside the submitted work. All the other authors have nothing to disclose.

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Fan, L., Liang, L., Wang, Y. et al. Glutamatergic basis of antipsychotic response in first-episode psychosis: a dual voxel study of the anterior cingulate cortex. Neuropsychopharmacol. 49, 845–853 (2024). https://doi.org/10.1038/s41386-023-01741-x

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