Glutamatergic Neurometabolite Levels in Patients With Ultra-Treatment-Resistant Schizophrenia

A Cross-Sectional 3T Proton Magnetic Resonance Spectroscopy Study

Yusuke Iwata, Shinichiro Nakajima, Eric Plitman, Fernando Caravaggio, Julia Kim, Parita Shah, Wanna Mar, Sofia Chavez, Vincenzo De Luca, Masaru Mimura, Gary Remington, Philip Gerretsen, Ariel Graff-Guerrero

Research output: Contribution to journalArticle

5 Citations (Scopus)

Abstract

Background: In terms of antipsychotic treatment response, patients with schizophrenia can be classified into three groups: 1) treatment resistant to both non-clozapine (non-CLZ) antipsychotics and CLZ (ultra-treatment-resistant schizophrenia [URS]), 2) treatment resistant to non-CLZ antipsychotics but CLZ-responsive schizophrenia [non-URS]), and 3) responsive to first-line antipsychotics (non-treatment-resistant schizophrenia). This study aimed to compare glutamatergic neurometabolite levels among these three patient groups and healthy control subjects using proton magnetic resonance spectroscopy. Methods: Glutamate and glutamate+glutamine levels were assessed in the caudate, the dorsal anterior cingulate cortex (dACC), and the dorsolateral prefrontal cortex using 3T proton magnetic resonance spectroscopy (point-resolved spectroscopy, echo time = 35 ms). Glutamatergic neurometabolite levels were compared between the groups. Results: A total of 100 participants were included, consisting of 26 patients with URS, 27 patients with non-URS, 21 patients with non-treatment-resistant schizophrenia, and 26 healthy control subjects. Group differences were detected in ACC glutamate+glutamine levels (F3,96 = 2.93, p =.038); patients with URS showed higher dACC glutamate+glutamine levels than healthy control subjects (p =.038). There were no group differences in the caudate or dorsolateral prefrontal cortex. Conclusions: Taken together with previous studies that demonstrated higher ACC glutamate levels in patients with treatment-resistant schizophrenia, this study suggests that higher levels of ACC glutamatergic metabolites may be among the shared biological characteristics of treatment resistance to antipsychotics, including CLZ.

Original languageEnglish
JournalBiological Psychiatry
DOIs
Publication statusAccepted/In press - 2018 Jan 1

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Schizophrenia
Antipsychotic Agents
Glutamic Acid
Glutamine
Therapeutics
Healthy Volunteers
Gyrus Cinguli
Prefrontal Cortex
Proton Magnetic Resonance Spectroscopy
Spectrum Analysis
Control Groups

Keywords

  • H-MRS
  • Antipsychotic
  • Clozapine
  • Glutamate
  • Schizophrenia
  • Treatment-resistant

ASJC Scopus subject areas

  • Biological Psychiatry

Cite this

Glutamatergic Neurometabolite Levels in Patients With Ultra-Treatment-Resistant Schizophrenia : A Cross-Sectional 3T Proton Magnetic Resonance Spectroscopy Study. / Iwata, Yusuke; Nakajima, Shinichiro; Plitman, Eric; Caravaggio, Fernando; Kim, Julia; Shah, Parita; Mar, Wanna; Chavez, Sofia; De Luca, Vincenzo; Mimura, Masaru; Remington, Gary; Gerretsen, Philip; Graff-Guerrero, Ariel.

In: Biological Psychiatry, 01.01.2018.

Research output: Contribution to journalArticle

Iwata, Yusuke ; Nakajima, Shinichiro ; Plitman, Eric ; Caravaggio, Fernando ; Kim, Julia ; Shah, Parita ; Mar, Wanna ; Chavez, Sofia ; De Luca, Vincenzo ; Mimura, Masaru ; Remington, Gary ; Gerretsen, Philip ; Graff-Guerrero, Ariel. / Glutamatergic Neurometabolite Levels in Patients With Ultra-Treatment-Resistant Schizophrenia : A Cross-Sectional 3T Proton Magnetic Resonance Spectroscopy Study. In: Biological Psychiatry. 2018.
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abstract = "Background: In terms of antipsychotic treatment response, patients with schizophrenia can be classified into three groups: 1) treatment resistant to both non-clozapine (non-CLZ) antipsychotics and CLZ (ultra-treatment-resistant schizophrenia [URS]), 2) treatment resistant to non-CLZ antipsychotics but CLZ-responsive schizophrenia [non-URS]), and 3) responsive to first-line antipsychotics (non-treatment-resistant schizophrenia). This study aimed to compare glutamatergic neurometabolite levels among these three patient groups and healthy control subjects using proton magnetic resonance spectroscopy. Methods: Glutamate and glutamate+glutamine levels were assessed in the caudate, the dorsal anterior cingulate cortex (dACC), and the dorsolateral prefrontal cortex using 3T proton magnetic resonance spectroscopy (point-resolved spectroscopy, echo time = 35 ms). Glutamatergic neurometabolite levels were compared between the groups. Results: A total of 100 participants were included, consisting of 26 patients with URS, 27 patients with non-URS, 21 patients with non-treatment-resistant schizophrenia, and 26 healthy control subjects. Group differences were detected in ACC glutamate+glutamine levels (F3,96 = 2.93, p =.038); patients with URS showed higher dACC glutamate+glutamine levels than healthy control subjects (p =.038). There were no group differences in the caudate or dorsolateral prefrontal cortex. Conclusions: Taken together with previous studies that demonstrated higher ACC glutamate levels in patients with treatment-resistant schizophrenia, this study suggests that higher levels of ACC glutamatergic metabolites may be among the shared biological characteristics of treatment resistance to antipsychotics, including CLZ.",
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author = "Yusuke Iwata and Shinichiro Nakajima and Eric Plitman and Fernando Caravaggio and Julia Kim and Parita Shah and Wanna Mar and Sofia Chavez and {De Luca}, Vincenzo and Masaru Mimura and Gary Remington and Philip Gerretsen and Ariel Graff-Guerrero",
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T2 - A Cross-Sectional 3T Proton Magnetic Resonance Spectroscopy Study

AU - Iwata, Yusuke

AU - Nakajima, Shinichiro

AU - Plitman, Eric

AU - Caravaggio, Fernando

AU - Kim, Julia

AU - Shah, Parita

AU - Mar, Wanna

AU - Chavez, Sofia

AU - De Luca, Vincenzo

AU - Mimura, Masaru

AU - Remington, Gary

AU - Gerretsen, Philip

AU - Graff-Guerrero, Ariel

PY - 2018/1/1

Y1 - 2018/1/1

N2 - Background: In terms of antipsychotic treatment response, patients with schizophrenia can be classified into three groups: 1) treatment resistant to both non-clozapine (non-CLZ) antipsychotics and CLZ (ultra-treatment-resistant schizophrenia [URS]), 2) treatment resistant to non-CLZ antipsychotics but CLZ-responsive schizophrenia [non-URS]), and 3) responsive to first-line antipsychotics (non-treatment-resistant schizophrenia). This study aimed to compare glutamatergic neurometabolite levels among these three patient groups and healthy control subjects using proton magnetic resonance spectroscopy. Methods: Glutamate and glutamate+glutamine levels were assessed in the caudate, the dorsal anterior cingulate cortex (dACC), and the dorsolateral prefrontal cortex using 3T proton magnetic resonance spectroscopy (point-resolved spectroscopy, echo time = 35 ms). Glutamatergic neurometabolite levels were compared between the groups. Results: A total of 100 participants were included, consisting of 26 patients with URS, 27 patients with non-URS, 21 patients with non-treatment-resistant schizophrenia, and 26 healthy control subjects. Group differences were detected in ACC glutamate+glutamine levels (F3,96 = 2.93, p =.038); patients with URS showed higher dACC glutamate+glutamine levels than healthy control subjects (p =.038). There were no group differences in the caudate or dorsolateral prefrontal cortex. Conclusions: Taken together with previous studies that demonstrated higher ACC glutamate levels in patients with treatment-resistant schizophrenia, this study suggests that higher levels of ACC glutamatergic metabolites may be among the shared biological characteristics of treatment resistance to antipsychotics, including CLZ.

AB - Background: In terms of antipsychotic treatment response, patients with schizophrenia can be classified into three groups: 1) treatment resistant to both non-clozapine (non-CLZ) antipsychotics and CLZ (ultra-treatment-resistant schizophrenia [URS]), 2) treatment resistant to non-CLZ antipsychotics but CLZ-responsive schizophrenia [non-URS]), and 3) responsive to first-line antipsychotics (non-treatment-resistant schizophrenia). This study aimed to compare glutamatergic neurometabolite levels among these three patient groups and healthy control subjects using proton magnetic resonance spectroscopy. Methods: Glutamate and glutamate+glutamine levels were assessed in the caudate, the dorsal anterior cingulate cortex (dACC), and the dorsolateral prefrontal cortex using 3T proton magnetic resonance spectroscopy (point-resolved spectroscopy, echo time = 35 ms). Glutamatergic neurometabolite levels were compared between the groups. Results: A total of 100 participants were included, consisting of 26 patients with URS, 27 patients with non-URS, 21 patients with non-treatment-resistant schizophrenia, and 26 healthy control subjects. Group differences were detected in ACC glutamate+glutamine levels (F3,96 = 2.93, p =.038); patients with URS showed higher dACC glutamate+glutamine levels than healthy control subjects (p =.038). There were no group differences in the caudate or dorsolateral prefrontal cortex. Conclusions: Taken together with previous studies that demonstrated higher ACC glutamate levels in patients with treatment-resistant schizophrenia, this study suggests that higher levels of ACC glutamatergic metabolites may be among the shared biological characteristics of treatment resistance to antipsychotics, including CLZ.

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KW - Schizophrenia

KW - Treatment-resistant

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