Glutamatergic Neurometabolite Levels in Patients With Ultra-Treatment-Resistant Schizophrenia: A Cross-Sectional 3T Proton Magnetic Resonance Spectroscopy Study

• Published in: Biological psychiatry (1969) Vol. 85; no. 7; pp. 596 - 605
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.04.2019
• Subjects: 1H-MRS; Adult; Antipsychotic; Antipsychotic Agents - pharmacology; Caudate Nucleus - diagnostic imaging; Caudate Nucleus - metabolism; Clozapine; Cross-Sectional Studies; Female; Glutamate; Glutamic Acid - metabolism; Glutamine - metabolism; Gyrus Cinguli - diagnostic imaging; Gyrus Cinguli - metabolism; Humans; Male; Middle Aged; Prefrontal Cortex - diagnostic imaging; Prefrontal Cortex - metabolism; Proton Magnetic Resonance Spectroscopy; Psychiatric/Mental Health; Schizophrenia; Schizophrenia - diagnostic imaging; Schizophrenia - drug therapy; Schizophrenia - metabolism; Treatment-resistant; Treatment-resistant; Schizophrenia; 1H-MRS; Antipsychotic; Clozapine; Glutamate; H-MRS
• ISSN: 0006-3223; 1873-2402; 1873-2402
• DOI: 10.1016/j.biopsych.2018.09.009

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. 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. 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. 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.