Subtype-specific alterations of gamma-aminobutyric acid and glutamate in patients with major depression.

BACKGROUND Measurement of cortical gamma-aminobutyric acid (GABA) and glutamate concentrations is possible using proton magnetic resonance spectroscopy. An initial report, using this technique, suggested that occipital cortex GABA concentrations are reduced in patients with major depressive disorder (MDD) relative to healthy comparison subjects. OBJECTIVES To replicate the GABA findings in a larger sample of MDD patients, to examine the clinical correlates of the GABA reductions in these subjects, and to examine other critical metabolite levels. DESIGN Study for association. SETTING Academic clinical research program. PARTICIPANTS The GABA measurements were made on 38 healthy control subjects and 33 depressed subjects. INTERVENTIONS Occipital cortex metabolite levels were measured using proton magnetic resonance spectroscopy. MAIN OUTCOME MEASURES The levels of occipital cortex GABA, glutamate, N-acetylaspartate, aspartate, creatine, and choline-containing compounds, along with several measures of tissue composition, were compared between the 2 groups. RESULTS Depressed subjects had significantly lower occipital cortex GABA concentrations compared with healthy controls (P =.01). In addition, mean glutamate levels were significantly increased in depressed subjects compared with healthy controls (P<.001). Significant reductions in the percentage of solid tissue (P =.009) and the percentage of white matter (P =.04) in the voxel were also observed. An examination of a combined database including subjects from the original study suggests that GABA and glutamate concentrations differ among MDD subtypes. CONCLUSIONS The study replicates the findings of decreased GABA concentrations in the occipital cortex of subjects with MDD. It also demonstrates that there is a change in the ratio of excitatory-inhibitory neurotransmitter levels in the cortex of depressed subjects that may be related to altered brain function. Last, the combined data set suggests that magnetic resonance spectroscopy GABA measures may serve as a biological marker for a subtype of MDD.

[1]  Arthur W Toga,et al.  Mapping brain size and cortical gray matter changes in elderly depression , 2003, Biological Psychiatry.

[2]  Jullie W Pan,et al.  Quantitative 31P spectroscopic imaging of human brain at 4 Tesla: Assessment of gray and white matter differences of phosphocreatine and ATP , 2001, Magnetic resonance in medicine.

[3]  A. Kudoh,et al.  Small-Dose Ketamine Improves the Postoperative State of Depressed Patients , 2002, Anesthesia and analgesia.

[4]  K. Rimvall,et al.  Regulation of γ‐Aminobutyric Acid Synthesis in the Brain , 1993 .

[5]  J. Price,et al.  Glial reduction in amygdala in major depressive disorder is due to oligodendrocytes , 2004, Biological Psychiatry.

[6]  P A Sargent,et al.  Brain serotonin1A receptor binding measured by positron emission tomography with [11C]WAY-100635: effects of depression and antidepressant treatment. , 2000, Archives of general psychiatry.

[7]  Takashi Ogino,et al.  Characterization of macromolecule resonances in the 1H NMR spectrum of rat brain , 1993, Magnetic resonance in medicine.

[8]  B. Roth,et al.  Morphometric evidence for neuronal and glial prefrontal cell pathology in major depression∗ ∗ See accompanying Editorial, in this issue. , 1999, Biological Psychiatry.

[9]  B. Shaywitz,et al.  CSF neurochemistry in depressed, manic, and schizophrenic patients compared with that of normal controls. , 1984, The American journal of psychiatry.

[10]  R. Gerner,et al.  CSF GABA in normal subjects and patients with depression, schizophrenia, mania, and anorexia nervosa. , 1981, The American journal of psychiatry.

[11]  J. Krystal,et al.  Beneficial effects of the antiglutamatergic agent riluzole in a patient diagnosed with obsessive-compulsive disorder and major depressive disorder , 2003, Psychopharmacology.

[12]  L. Selemon,et al.  Reductions in neuronal and glial density characterize the dorsolateral prefrontal cortex in bipolar disorder , 2001, Biological Psychiatry.

[13]  J. Price,et al.  Glial reduction in the subgenual prefrontal cortex in mood disorders. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[14]  J. Cousins,et al.  Neurobiochemical changes from Taxol/Neupogen chemotherapy for metastatic breast carcinoma corresponds with suicidal depression. , 1996, Cancer letters.

[15]  K. Behar,et al.  Measurement of GABA following GABA‐transaminase inhibition by gabaculine: A 1H and 31P NMR spectroscopic study of rat brain in vivo , 1994, Magnetic resonance in medicine.

[16]  M. Mauri,et al.  Plasma and Platelet Amino Acid Concentrations in Patients Affected by Major Depression and under Fluvoxamine Treatment , 1998, Neuropsychobiology.

[17]  F. Petty.  GABA and mood disorders: a brief review and hypothesis. , 1995, Journal of affective disorders.

[18]  H. Meltzer,et al.  Plasma concentrations of excitatory amino acids, serine, glycine, taurine and histidine in major depression , 1995, European Neuropsychopharmacology.

[19]  M. Wiesmann,et al.  S-100B is increased in melancholic but not in non-melancholic major depression. , 2001, Journal of affective disorders.

[20]  Bernadette Lipinski,et al.  Reduced glutamate in the anterior cingulate cortex in depression: an in vivo proton magnetic resonance spectroscopy study , 2000, Biological Psychiatry.

[21]  G. Rajkowska,et al.  Postmortem studies in mood disorders indicate altered numbers of neurons and glial cells , 2000, Biological Psychiatry.

[22]  H. Grabe,et al.  Neurotrophic Factor S100beta in Major Depression , 2001, Neuropsychobiology.

[23]  Abraham Weizman,et al.  Amantadine as augmentation therapy in the management of treatment-resistant depression , 2003, International clinical psychopharmacology.

[24]  Douglas L Rothman,et al.  Graded image segmentation of brain tissue in the presence of inhomogeneous radio frequency fields. , 2002, Magnetic resonance imaging.

[25]  Ulf Ziemann,et al.  Rapid modulation of GABA in sensorimotor cortex induced by acute deafferentation , 2002, Annals of neurology.

[26]  John H Krystal,et al.  Antidepressant effects of ketamine in depressed patients , 2000, Biological Psychiatry.

[27]  G. Rajkowska,et al.  Glial fibrillary acidic protein immunoreactivity in the prefrontal cortex distinguishes younger from older adults in major depressive disorder , 2000, Biological Psychiatry.

[28]  M. Schroeter,et al.  S100B is increased in mood disorders and may be reduced by antidepressive treatment , 2002, Neuroreport.

[29]  Jullie W Pan,et al.  Quantitative 1H spectroscopic imaging of human brain at 4.1 T using image segmentation , 1996, Magnetic resonance in medicine.

[30]  R. Yolken,et al.  Immunohistochemical Localization of Phosphorylated Glial Fibrillary Acidic Protein in the Prefrontal Cortex and Hippocampus from Patients with Schizophrenia, Bipolar Disorder, and Depression , 2001, Brain, Behavior, and Immunity.

[31]  G F Mason,et al.  Glutamate and GABA systems as targets for novel antidepressant and mood-stabilizing treatments , 2002, Molecular Psychiatry.

[32]  C. Pariante,et al.  Glial cell abnormalities in major psychiatric disorders: the evidence and implications , 2001, Brain Research Bulletin.

[33]  R. Roth,et al.  GABA levels in CSF of patients with psychiatric disorders. , 1980, The American journal of psychiatry.

[34]  K. Behar,et al.  Analysis of macromolecule resonances in 1H NMR spectra of human brain , 1994, Magnetic resonance in medicine.

[35]  M. Erecińska,et al.  Regulation of GABA Level in Rat Brain Synaptosomes: Fluxes Through Enzymes of the GABA Shunt and Effects of Glutamate, Calcium, and Ketone Bodies , 1996, Journal of neurochemistry.

[36]  D. Pickar,et al.  CSF GABA in depressed patients and normal controls , 1989, Biological Psychiatry.

[37]  Robert G. Shulman,et al.  Energy on Demand , 1999, Science.

[38]  J. Krystal,et al.  Increased occipital cortex GABA concentrations in depressed patients after therapy with selective serotonin reuptake inhibitors. , 2002, The American journal of psychiatry.

[39]  J. Price,et al.  Low glial numbers in the amygdala in major depressive disorder , 2002, Biological Psychiatry.

[40]  U Klose,et al.  Proton MR spectroscopy with metabolite-nulling reveals elevated macromolecules in acute multiple sclerosis. , 2001, Brain : a journal of neurology.

[41]  A. Alavi,et al.  Regional cerebral glucose metabolism in late-life depression and Alzheimer disease: a preliminary positron emission tomography study. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[42]  Peter Herscovitch,et al.  Regional cerebral glucose utilization in patients with a range of severities of unipolar depression , 2002, Biological Psychiatry.

[43]  G. Rajkowska,et al.  Glia pathology in the prefrontal cortex in alcohol dependence with and without depressive symptoms , 2002, Biological Psychiatry.

[44]  E. Vandoolaeghe,et al.  Serum levels of excitatory amino acids, serine, glycine, histidine, threonine, taurine, alanine and arginine in treatment‐resistant depression: modulation by treatment with antidepressants and prediction of clinical responsivity , 1998, Acta psychiatrica Scandinavica.

[45]  Christine L Larson,et al.  Brain electrical tomography in depression: the importance of symptom severity, anxiety, and melancholic features , 2002, Biological Psychiatry.

[46]  Robert Bartha,et al.  Quantitative proton short‐echo‐time LASER spectroscopy of normal human white matter and hippocampus at 4 Tesla incorporating macromolecule subtraction , 2003, Magnetic resonance in medicine.

[47]  R. Post,et al.  Lack of effect of carbamazepine on gamma‐aminobutyric acid in cerebrospinal fluid , 1980, Neurology.

[48]  S. Otsuki,et al.  Cerebrospinal fluid gamma-aminobutyric acid and homovanillic acid in depressive disorders. , 1982, Biological psychiatry.

[49]  K. Behar,et al.  Short echo time proton magnetic resonance spectroscopic imaging of macromolecule and metabolite signal intensities in the human brain , 1996, Magnetic resonance in medicine.

[50]  J. Krystal,et al.  Increased cortical GABA concentrations in depressed patients receiving ECT. , 2003, The American journal of psychiatry.

[51]  D. Rothman,et al.  Improvements on an in Vivo automatic shimming method (FASTERMAP) , 1997, Magnetic resonance in medicine.

[52]  D. Schulz,et al.  Prolonged effect of an anesthetic dose of ketamine on behavioral despair , 2002, Pharmacology Biochemistry and Behavior.

[53]  D. Kupfer,et al.  Pet imaging of serotonin 1A receptor binding in depression , 1999, Biological Psychiatry.

[54]  K. Behar,et al.  A Neuronal Glutamate Transporter Contributes to Neurotransmitter GABA Synthesis and Epilepsy , 2002, The Journal of Neuroscience.

[55]  Fahmeed Hyder,et al.  Reduced Cortical γ-Aminobutyric Acid Levels in Depressed Patients Determined by Proton Magnetic Resonance Spectroscopy , 1999 .

[56]  D L Rothman,et al.  Spectroscopic Assessment of Alterations in Macromolecule and Small-Molecule Metabolites in Human Brain After Stroke , 2001, Stroke.

[57]  R. Mattson,et al.  Localized 1H NMR measurements of gamma-aminobutyric acid in human brain in vivo. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[58]  K. Petersen,et al.  Astroglial Contribution to Brain Energy Metabolism in Humans Revealed by 13C Nuclear Magnetic Resonance Spectroscopy: Elucidation of the Dominant Pathway for Neurotransmitter Glutamate Repletion and Measurement of Astrocytic Oxidative Metabolism , 2002, The Journal of Neuroscience.

[59]  V. Arolt,et al.  Neurotrophic Effects of Electroconvulsive Therapy: A Proton Magnetic Resonance Study of the Left Amygdalar Region in Patients with Treatment-Resistant Depression , 2003, Neuropsychopharmacology.

[60]  J. Alger,et al.  High‐field proton magnetic resonance spectroscopy of human cerebrum obtained during surgery for epilepsy , 1989, Neurology.

[61]  Wolfgang Grodd,et al.  Proton MRS in Kennedy disease: Absolute metabolite and macromolecular concentrations , 2002, Journal of magnetic resonance imaging : JMRI.

[62]  K. Behar,et al.  Glutamine is the major precursor for GABA synthesis in rat neocortex in vivo following acute GABA-transaminase inhibition , 2001, Brain Research.

[63]  G. Tunnicliff,et al.  Central GABAergic Systems and Depressive Illness , 2003, Neurochemical Research.

[64]  G. Crane.  Cyloserine as an antidepressant agent. , 1959, The American journal of psychiatry.

[65]  A. Rush,et al.  Low plasma γ-aminobutyric acid levels in male patients with depression , 1992, Biological Psychiatry.

[66]  L. Yatham,et al.  GABA function in mood disorders: an update and critical review. , 1998, Life sciences.

[67]  Sung-Cheng Huang,et al.  Differential cerebral metabolic changes with paroxetine treatment of obsessive-compulsive disorder vs major depression. , 2002, Archives of general psychiatry.

[68]  V. Arango,et al.  Attenuated 5‐HT1A receptor signaling in brains of suicide victims: involvement of adenylyl cyclase, phosphatidylinositol 3‐kinase, Akt and mitogen‐activated protein kinase , 2003, Journal of neurochemistry.

[69]  J. Krystal,et al.  Impairment of GABAergic transmission in depression: new insights from neuroimaging studies. , 2000, Critical reviews in neurobiology.

[70]  P. Brambilla,et al.  GABAergic dysfunction in mood disorders , 2003, Molecular Psychiatry.