Glutamatergic neurometabolites and cortical thickness in treatment-resistant schizophrenia: Implications for glutamate-mediated excitotoxicity

Parita Shah, Eric Plitman, Yusuke Iwata, Julia Kim, Shinichiro Nakajima, Nathan Chan, Eric E. Brown, Fernando Caravaggio, Edgardo Torres, Margaret Hahn, M. Mallar Chakravarty, Gary Remington, Philip Gerretsen, Ariel Graff-Guerrero

Research output: Contribution to journalArticlepeer-review

23 Citations (Scopus)


Treatment-resistant schizophrenia may be related to structural brain alterations. However, the mechanisms underlying these changes remain unclear. The present study had two main aims: (1) to explore differences in cortical thickness between patients with treatment-resistant schizophrenia non-responsive to clozapine (ultra-treatment-resistant schizophrenia, UTRS), patients with treatment-resistant schizophrenia responsive to clozapine (Cloz-Resp), patients responsive to first-line non-clozapine antipsychotics (FL-Resp), and healthy controls (HCs); and (2) to test our hypothesis of structural compromise as a manifestation of neurotoxic effects from elevated glutamate (Glu) (i.e. glutamate-mediated excitotoxicity) by examining the relationships between glutamatergic neurometabolite levels (Glu and glutamate + glutamine (Glx)) in the dorsal anterior cingulate cortex (dACC) and cortical thickness. T1-weighted images and 1H-MRS data were obtained from UTRS (n = 24), Cloz-Resp (n = 25), FL-Resp (n = 19), and HCs (n = 26). Vertex-wise analyses showed that patients with UTRS had widespread cortical thinning in the bilateral frontal, temporal, parietal, and occipital gyri compared to HCs and FL-Resp patients. In the patient group, negative associations were found between dACC Glx levels and cortical thickness in the right dorsolateral prefrontal cortex after correcting for multiple comparisons and controlling for age, sex, antipsychotic dose, and illness severity. In conclusion, glutamate-mediated excitotoxicity may be one of the mechanisms underlying structural compromise seen in treatment-resistant schizophrenia. Future studies should longitudinally examine the associations between glutamatergic neurometabolite levels and cortical thickness in the context of treatment and illness progression.

Original languageEnglish
Pages (from-to)151-158
Number of pages8
JournalJournal of Psychiatric Research
Publication statusPublished - 2020 May


  • Clozapine
  • Excitotoxicity
  • Glutamate
  • Schizophrenia
  • Thickness

ASJC Scopus subject areas

  • Psychiatry and Mental health
  • Biological Psychiatry


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