title: Anterior cingulate Glutamate-Glutamine cycle metabolites are altered in euthymic bipolar I disorder.
abstract: Bipolar disorder (BD) has been consistently associated with abnormalities in the Glutamate/GABA-Glutamine cycle. Magnetic resonance spectroscopy (MRS) studies have reported increased brain Glutamate (Glu) and Glx (Glu+Glutamine) in subjects with BD. However, data on separate measures of GABA and Glutamine (Gln) in BD are sparse due to overlapping resonant signals. The development of new sequence methods in the quantification of these metabolites has allowed a better understanding of the Glu/GABA-Gln cycle but data on this field of research remains sparse in BD. Eighty-eight subjects (50 euthymic BD and 38 HC) underwent 3T proton magnetic resonance spectroscopy (1H MRS) in the anterior cingulate cortex (ACC; 2×2×4.5cm(3)) using a two-dimensional JPRESS sequence. GABA, Glutamine (Gln) and Glutamate (Glu) were quantified with the ProFit program. Using image segmentation and known creatine (Cre) concentrations for white and grey matter, metabolite concentrations were calculated for the excited MRS voxel. GABA levels did not differ between groups. Gln level was higher in euthymic BD patients than in healthy controls. The Glu level and Glu/Gln ratio were lower in BD patients than in controls. The use of anticonvulsants was associated with Gln increase but did not affect Glu or Glu/Gln. Neither lithium nor antipsychotic use influenced metabolite levels. The ACC MRS findings indicate that the glutamatergic function in euthymic medicated BD patients is altered relative to controls. Whether this feature is a metabolic signature of euthymic BD subjects should be the focus of future studies.
authors.affiliation: Mood Disorders Unit (GRUDA), Institute of Psychiatry, School of Medicine, University of São Paulo (IPq-FMUSP), Brazil; Genetics and Pharmacogenetics Unit (PROGENE), Institute of Psychiatry, School of Medicine, University of São Paulo (IPq-FMUSP), Brazil. Electronic address: marciogss@gmail.com.
authors.forename: Márcio Gerhardt
authors.initials: MG
authors.lastname: Soeiro-de-Souza
authors.affiliation: Institute for Biomedical Engineering University and ETH Zurich, Switzerland; Max Planck Institute of Biological Cybernetics, Tübingen, Germany.
authors.forename: Anke
authors.initials: A
authors.lastname: Henning
authors.affiliation: National Institute of Mental Health, NIH, Bethesda, USA.
authors.forename: Rodrigo
authors.initials: R
authors.lastname: Machado-Vieira
authors.affiliation: Mood Disorders Unit (GRUDA), Institute of Psychiatry, School of Medicine, University of São Paulo (IPq-FMUSP), Brazil.
authors.forename: Ricardo A
authors.initials: RA
authors.lastname: Moreno
authors.affiliation: Laboratory of Magnetic Resonance LIM44, Department and Institute of Radiology, University of São Paulo (InRad-FMUSP), Brazil.
authors.forename: Bruno F
authors.initials: BF
authors.lastname: Pastorello
authors.affiliation: Laboratory of Magnetic Resonance LIM44, Department and Institute of Radiology, University of São Paulo (InRad-FMUSP), Brazil.
authors.forename: Cláudia
authors.initials: C
authors.lastname: da Costa Leite
authors.affiliation: Genetics and Pharmacogenetics Unit (PROGENE), Institute of Psychiatry, School of Medicine, University of São Paulo (IPq-FMUSP), Brazil.
authors.forename: Homero
authors.initials: H
authors.lastname: Vallada
authors.affiliation: Laboratory of Magnetic Resonance LIM44, Department and Institute of Radiology, University of São Paulo (InRad-FMUSP), Brazil.
authors.forename: Maria Concepcion Garcia
authors.initials: MC
authors.lastname: Otaduy
mesh_terms: D000293:Adolescent; D000328:Adult; D000704:Analysis of Variance; D000928:Antidepressive Agents / Q000494:pharmacology / Q000627:therapeutic use; D001714:Bipolar Disorder / Q000188:drug therapy / Q000473:pathology*; D005260:Female; D018698:Glutamic Acid / Q000378:metabolism*; D005973:Glutamine / Q000378:metabolism*; D006179:Gyrus Cinguli / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D013058:Mass Spectrometry; D008875:Middle Aged; D055815:Young Adult; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
chemical_list: D000928:Antidepressive Agents; D005973:Glutamine; D018698:Glutamic Acid; D005680:gamma-Aminobutyric Acid
keywords: Bipolar; GABA; Glutamate; Glutamine; Spectroscopy