title: Glutamatergic neurometabolites in clozapine-responsive and -resistant schizophrenia.
abstract: BACKGROUND
  According to the current schizophrenia treatment guidelines, 3 levels of responsiveness to antipsychotic medication exist: those who respond to first-line antipsychotics, those with treatment-resistant schizophrenia who respond to clozapine, and those with clozapine-resistant or ultra-treatment resistant schizophrenia. Proton magnetic resonance spectroscopy studies indicate that antipsychotic medication decreases glutamate or total glutamate + glutamine in the brains of patients with schizophrenia and may represent a biomarker of treatment response; however, the 3 levels of treatment responsiveness have not been evaluated.
  
  
  METHODS
  Proton magnetic resonance spectroscopy spectra were acquired at 3 Tesla from patients taking a second generation non-clozapine antipsychotic (first-line responders), patients with treatment-resistant schizophrenia taking clozapine, patients with ultra-treatment resistant schizophrenia taking a combination of antipsychotics, and healthy comparison subjects.
  
  
  RESULTS
  Group differences in cerebrospinal fluid-corrected total glutamate + glutamine levels scaled to creatine were detected in the dorsolateral prefrontal cortex [df(3,48); F = 3.07, P = .04, partial η(2) = 0.16] and the putamen [df(3,32); F = 2.93, P = .05, partial η(2) = 0.22]. The first-line responder group had higher dorsolateral prefrontal cortex total glutamate + glutamine levels scaled to creatine than those with ultra-treatment resistant schizophrenia [mean difference = 0.25, standard error = 0.09, P = .04, family-wise error-corrected]. Those with treatment-resistant schizophrenia had higher total glutamate + glutamine levels scaled to creatine in the putamen than the first-line responders (mean difference = 0.31, standard error = 0.12, P = .05, family-wise error-corrected) and those with ultra-treatment-resistant schizophrenia (mean difference = 0.39, standard error = 0.12, P = .02, family-wise error-corrected).
  
  
  CONCLUSIONS
  Total glutamate + glutamine levels scaled to creatine in the putamen may represent a marker of response to clozapine. Future studies should investigate glutamatergic anomalies prior to clozapine initiation and following successful treatment.
authors.affiliation: Department of Psychiatry, University of California, San Diego, CA (Dr Goldstein); School of Pharmacy and Centre for Brain Research, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand (Drs Goldstein, Anderson, and Russell and Mr Pillai); Centre for Brain Research and Department of Psychological Medicine, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand (Dr Kydd).
authors.forename: Meghan Elizabeth
authors.initials: ME
authors.lastname: Goldstein
authors.affiliation: Department of Psychiatry, University of California, San Diego, CA (Dr Goldstein); School of Pharmacy and Centre for Brain Research, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand (Drs Goldstein, Anderson, and Russell and Mr Pillai); Centre for Brain Research and Department of Psychological Medicine, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand (Dr Kydd).
authors.forename: Valerie Margaret
authors.initials: VM
authors.lastname: Anderson
authors.affiliation: Department of Psychiatry, University of California, San Diego, CA (Dr Goldstein); School of Pharmacy and Centre for Brain Research, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand (Drs Goldstein, Anderson, and Russell and Mr Pillai); Centre for Brain Research and Department of Psychological Medicine, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand (Dr Kydd).
authors.forename: Avinesh
authors.initials: A
authors.lastname: Pillai
authors.affiliation: Department of Psychiatry, University of California, San Diego, CA (Dr Goldstein); School of Pharmacy and Centre for Brain Research, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand (Drs Goldstein, Anderson, and Russell and Mr Pillai); Centre for Brain Research and Department of Psychological Medicine, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand (Dr Kydd).
authors.forename: Robert R
authors.initials: RR
authors.lastname: Kydd
authors.affiliation: Department of Psychiatry, University of California, San Diego, CA (Dr Goldstein); School of Pharmacy and Centre for Brain Research, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand (Drs Goldstein, Anderson, and Russell and Mr Pillai); Centre for Brain Research and Department of Psychological Medicine, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand (Dr Kydd). b.russell@auckland.ac.nz.
authors.forename: Bruce R
authors.initials: BR
authors.lastname: Russell
mesh_terms: D000328:Adult; D014150:Antipsychotic Agents / Q000627:therapeutic use*; D015415:Biomarkers / Q000134:cerebrospinal fluid; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D016022:Case-Control Studies; D003024:Clozapine / Q000627:therapeutic use*; D003401:Creatine / Q000134:cerebrospinal fluid; D004351:Drug Resistance; D004359:Drug Therapy, Combination; D005260:Female; D018698:Glutamic Acid / Q000134:cerebrospinal fluid*; D005973:Glutamine / Q000134:cerebrospinal fluid*; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D066244:Proton Magnetic Resonance Spectroscopy; D012559:Schizophrenia / Q000134:cerebrospinal fluid / Q000175:diagnosis / Q000188:drug therapy*; D012565:Schizophrenic Psychology; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D014150:Antipsychotic Agents; D015415:Biomarkers; D005973:Glutamine; D018698:Glutamic Acid; D003024:Clozapine; D003401:Creatine
keywords: antipsychotic; clozapine; glutamate; magnetic resonance imaging; schizophrenia