Striatal glutamate, subcortical structure and clinical response to first-line treatment in first-episode psychosis patients

Prog Neuropsychopharmacol Biol Psychiatry. 2022 Mar 8;113:110473. doi: 10.1016/j.pnpbp.2021.110473. Epub 2021 Nov 6.


Introduction: Recent studies have observed that patients with treatment-resistant schizophrenia as well as patients with schizophrenia who do not respond within a medication trial exhibit excess activity of the glutamate system. In this study we sought to replicate the within-trial glutamate abnormality and to investigate the potential for structural differences and treatment-induced changes to improve identification of medication responders and non-responders.

Methods: We enrolled 48 medication-naïve patients in a 4-week trial of risperidone and classified them retrospectively into responders and non-responders using clinical criteria. Proton magnetic resonance spectroscopy and T1-weighted structural MRI were acquired pre- and post-treatment to quantify striatal glutamate levels and several measures of subcortical brain structure.

Results: Patients were classified as 29 responders and 19 non-responders. Striatal glutamate was higher in the non-responders than responders both pre- and post-treatment (F1,39 = 7.15, p = .01). Volumetric measures showed a significant group x time interaction (t = 5.163, <1%FDR), and group x time x glutamate interaction (t = 4.23, <15%FDR) were seen in several brain regions. Striatal volumes increased at trend level with treatment in both groups, and a positive association of striatal volumes with glutamate levels was seen in the non-responders.

Conclusions: Combining anatomic measures with glutamate levels offers the potential to enhance classification of responders and non-responders to antipsychotic medications as well as to provide mechanistic understanding of the interplay between neuroanatomical and neurochemical changes induced by these medications. Ethical statement The study was approved by the Ethics and Scientific committees of the Instituto Nacional de Neurología y Neurocirugía in Mexico City. All participants over 18 years fully understood and signed the informed consent; in case the patient was under 18 years, informed consent was obtained from both parents. Participants did not receive a stipend.

Keywords: Antipsychotic treatment; Brain volume analysis; First episode; Glutamate; Magnetic resonance spectroscopy; Schizophrenia.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Brain / metabolism
  • Corpus Striatum* / drug effects
  • Corpus Striatum* / metabolism
  • Female
  • Glutamic Acid / metabolism*
  • Humans
  • Image Processing, Computer-Assisted
  • Magnetic Resonance Imaging
  • Male
  • Proton Magnetic Resonance Spectroscopy
  • Psychotic Disorders* / drug therapy
  • Psychotic Disorders* / metabolism
  • Retrospective Studies
  • Risperidone / administration & dosage*
  • Risperidone / pharmacology
  • Schizophrenia, Treatment-Resistant* / drug therapy
  • Schizophrenia, Treatment-Resistant* / metabolism
  • Serotonin Antagonists / administration & dosage*
  • Serotonin Antagonists / pharmacology
  • Surveys and Questionnaires
  • Young Adult


  • Serotonin Antagonists
  • Glutamic Acid
  • Risperidone