title: Changes in plasma D-serine, L-serine, and glycine levels in treatment-resistant schizophrenia before and after clozapine treatment.
abstract: Hypofunction of the N-methyl-d-aspartate (NMDA) subtype of glutamate receptors may be involved in the pathophysiology of schizophrenia. Many studies have investigated peripheral NMDA receptor-related glutamatergic amino acid levels because of their potential as biological markers. Peripheral d-serine levels and the ratio of d-serine to total serine have been reported to be significantly lower in patients with schizophrenia than in controls. Peripheral d-serine levels and the d-/l-serine ratio have also been reported to significantly increase in patients with schizophrenia as their clinical symptoms improve from the time of admission to the time of discharge. In this study, we examined whether peripheral NMDA receptor-related glutamatergic amino acids levels were altered in patients with treatment-resistant schizophrenia compared to controls and whether these peripheral amino acids levels were altered by clozapine treatment. Twenty-two patients with treatment-resistant schizophrenia and 22 age- and gender-matched healthy controls were enrolled. The plasma levels of d-serine, l-serine, glycine, glutamate, and glutamine were measured before and after clozapine treatment. We found that the plasma levels of d-serine and the d-/l-serine ratio were significantly lower in the patients before clozapine treatment than in the controls. The d-/l-serine ratio was significantly increased by clozapine treatment in patients, and no significant difference was observed in the plasma levels of d-serine and the d-/l-serine ratio between the patients after clozapine treatment and the controls. We also found that plasma glycine levels and the glycine/l-serine ratio were significantly increased following clozapine treatment in the patients, and the glycine/l-serine ratio was significantly higher in the patients after clozapine treatment than in the controls. There was no significant difference in the plasma levels of glutamate and glutamine both between the controls and patients and between before and after clozapine treatment. This study firstly demonstrated changes of d-/l-serine and glycine/l-serine ratio between before and after clozapine treatment, suggesting that the plasma d-/l-serine ratio and glycine/l-serine ratio could be markers of therapeutic efficacy or clinical state in treatment-resistant schizophrenia.
authors.affiliation: Department of Molecular Neuropsychiatry, Osaka University Graduate School of Medicine, Suita, Osaka 5650871, Japan; Department of Psychiatry, Osaka University Graduate School of Medicine, Suita, Osaka 5650871, Japan.
authors.forename: Hidenaga
authors.initials: H
authors.lastname: Yamamori
authors.affiliation: Department of Psychiatry, Osaka University Graduate School of Medicine, Suita, Osaka 5650871, Japan; Molecular Research Center for Children's Mental Development, United Graduate School of Child Development, Osaka University, Suita, Osaka 5650871, Japan. Electronic address: hashimor@psy.med.osaka-u.ac.jp.
authors.forename: Ryota
authors.initials: R
authors.lastname: Hashimoto
authors.affiliation: Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health, Chiba, Chiba 2608670, Japan.
authors.forename: Yuko
authors.initials: Y
authors.lastname: Fujita
authors.affiliation: Department of Psychiatry, Course of Integrated Brain Sciences, Medical Informatics, Institute of Health Bioscience, The University of Tokushima Graduate School, Tokushima, Tokushima 7708503, Japan.
authors.forename: Shusuke
authors.initials: S
authors.lastname: Numata
authors.affiliation: Department of Psychiatry, Osaka University Graduate School of Medicine, Suita, Osaka 5650871, Japan.
authors.forename: Yuka
authors.initials: Y
authors.lastname: Yasuda
authors.affiliation: Department of Psychiatry, Osaka University Graduate School of Medicine, Suita, Osaka 5650871, Japan.
authors.forename: Michiko
authors.initials: M
authors.lastname: Fujimoto
authors.affiliation: Department of Psychiatry, Osaka University Graduate School of Medicine, Suita, Osaka 5650871, Japan.
authors.forename: Kazutaka
authors.initials: K
authors.lastname: Ohi
authors.affiliation: Department of Molecular Neuropsychiatry, Osaka University Graduate School of Medicine, Suita, Osaka 5650871, Japan.
authors.forename: Satomi
authors.initials: S
authors.lastname: Umeda-Yano
authors.affiliation: Department of Molecular Neuropsychiatry, Osaka University Graduate School of Medicine, Suita, Osaka 5650871, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Ito
authors.affiliation: Department of Psychiatry, Course of Integrated Brain Sciences, Medical Informatics, Institute of Health Bioscience, The University of Tokushima Graduate School, Tokushima, Tokushima 7708503, Japan.
authors.forename: Tetsuro
authors.initials: T
authors.lastname: Ohmori
authors.affiliation: Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health, Chiba, Chiba 2608670, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Hashimoto
authors.affiliation: Department of Psychiatry, Osaka University Graduate School of Medicine, Suita, Osaka 5650871, Japan.
authors.forename: Masatoshi
authors.initials: M
authors.lastname: Takeda
mesh_terms: D000328:Adult; D014150:Antipsychotic Agents / Q000627:therapeutic use*; D016022:Case-Control Studies; D003024:Clozapine / Q000627:therapeutic use*; D005260:Female; D018698:Glutamic Acid / Q000097:blood; D005973:Glutamine / Q000097:blood; D005998:Glycine / Q000097:blood*; D006801:Humans; D008297:Male; D008875:Middle Aged; D012559:Schizophrenia / Q000097:blood / Q000188:drug therapy*; D012694:Serine / Q000097:blood* / Q000737:chemistry; D013237:Stereoisomerism; D017211:Treatment Failure
chemical_list: D014150:Antipsychotic Agents; D005973:Glutamine; D018698:Glutamic Acid; D012694:Serine; D003024:Clozapine; D005998:Glycine
keywords: Clozapine; Glycine; Plasma; Serine; Treatment-resistant schizophrenia