Investigating structural subdivisions of the anterior cingulate cortex in schizophrenia, with implications for treatment resistance and glutamatergic levels

J Psychiatry Neurosci. 2022 Jan 13;47(1):E1-E10. doi: 10.1503/jpn.210113. Print 2022 Jan-Feb.


Background: Abnormalities in the anterior cingulate cortex (ACC) are thought to play an important role in the pathophysiology of schizophrenia. Given regional variations in ACC structure, the present study aimed to examine ACC structural subdivisions and their relationships to treatment resistance and glutamatergic levels in schizophrenia.

Methods: This study included 100 patients with schizophrenia and 52 healthy controls from 2 cohorts. We applied non-negative matrix factorization to identify accurate and stable spatial components of ACC structure. Between groups, we compared ACC structural indices in each spatial component based on treatment resistance or response and tested relationships with ACC glutamate + glutamine levels.

Results: We detected reductions in cortical thickness and increases in mean diffusivity in the spatial components on the surface of the cingulate sulcus, especially in patients with treatment-resistant and clozapine-resistant schizophrenia. Notably, mean diffusivity in these components was higher in patients who did not respond to clozapine compared to those who did. Furthermore, these ACC structural alterations were related to elevated ACC glutamate + glutamine levels but not related to symptomatology or antipsychotic dose.

Limitations: Sample sizes, cross-sectional findings and mixed antipsychotic status were limitations of this study.

Conclusion: This study identified reproducible abnormalities in ACC structures in patients with treatment-resistant and clozapine-resistant schizophrenia. Given that these spatial components play a role in inhibitory control, the present study strengthens the notion that glutamate-related disinhibition is a common biological feature of treatment resistance in schizophrenia.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antipsychotic Agents* / pharmacology
  • Antipsychotic Agents* / therapeutic use
  • Clozapine* / pharmacology
  • Clozapine* / therapeutic use
  • Cross-Sectional Studies
  • Glutamic Acid
  • Glutamine
  • Gyrus Cinguli / diagnostic imaging
  • Humans
  • Schizophrenia* / diagnostic imaging
  • Schizophrenia* / drug therapy


  • Antipsychotic Agents
  • Glutamine
  • Glutamic Acid
  • Clozapine