A Pilot In Vivo Proton Magnetic Resonance Spectroscopy Study of Amino Acid Neurotransmitter Response to Ketamine Treatment of Major Depressive Disorder

The N-methyl-D-aspartate receptor antagonist ketamine can improve major depressive disorder (MDD) within hours. To evaluate the putative role of glutamatergic and GABAergic systems in ketamine’s antidepressant action, medial prefrontal cortical (mPFC) levels of glutamate+glutamine (Glx) and γ-aminobutyric acid (GABA) were measured before, during, and after ketamine administration using proton magnetic resonance spectroscopy. Ketamine (0.5 mg kg−1 intravenously) was administered to 11 depressed patients with MDD. Glx and GABA mPFC responses were measured as ratios relative to unsuppressed voxel tissue water (W) successfully in 8/11 patients. Ten of 11 patients remitted (50% reduction in 24-item Hamilton Depression Rating Scale and total score ⩽10) within 230 min of commencing ketamine. mPFC Glx/W and GABA/W peaked at 37.8%±7.5% and 38.0%±9.1% above baseline in ~26 min. Mean areas under the curve for Glx/W (P=0.025) and GABA/W (P=0.005) increased and correlated (r=0.796; P=0.018). Clinical improvement correlated with 90-min norketamine concentration (df=6, r=−0.78, P=0.023), but no other measures.

[1]  M. Lorr,et al.  Profile of mood states , 1971 .

[2]  M. Lorr,et al.  Manual for the Profile of Mood States , 1971 .

[3]  B. Douglas,et al.  The effects of magnesium deficiency of ketamine sleeping times in the rat. , 1975, British journal of anaesthesia.

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

[5]  A. Rossier.  Letter to the Editor , 1986, Paraplegia.

[6]  F. Benes,et al.  Increased vertical axon numbers in cingulate cortex of schizophrenics. , 1987, Archives of general psychiatry.

[7]  P. Morselli,et al.  GABA and affective disorders. , 1987, Medical biology.

[8]  G. Skuza,et al.  The effect of CGP 37849 and CGP 39551, competitive NMDA receptor antagonists, in the forced swimming test. , 1992, Polish journal of pharmacology and pharmacy.

[9]  G. Skuza,et al.  Effects of MK-801 and antidepressant drugs in the forced swimming test in rats , 1992, European Neuropsychopharmacology.

[10]  R. Blasco,et al.  Selective Inhibition of Calcium Entry Induced by Benzylisoquinolines in Rat Smooth Muscle , 1992, The Journal of pharmacy and pharmacology.

[11]  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.

[12]  N. Nair,et al.  Biochemistry and pharmacology of reversible inhibitors of MAO-A agents: focus on moclobemide. , 1993, Journal of psychiatry & neuroscience : JPN.

[13]  Douglas H. Smith,et al.  Magnesium and ketamine attenuate cognitive dysfunction following experimental brain injury , 1993, Neuroscience Letters.

[14]  R. Porsolt,et al.  MK-801 and enantiomers: Potential antidepressants or false positives in classical screening models? , 1993, Pharmacology Biochemistry and Behavior.

[15]  M. Papp,et al.  Antidepressant activity of non-competitive and competitive NMDA receptor antagonists in a chronic mild stress model of depression. , 1994, European journal of pharmacology.

[16]  M. Ohayon,et al.  Modulation of the AMPA receptor by phospholipase A2: Effect of the antidepressant trimipramine , 1994, Psychiatry Research.

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

[18]  P. Skolnick,et al.  Antidepressant-like actions of the polyamine site NMDA antagonist, eliprodil (SL-82.0715) , 1995, Pharmacology Biochemistry and Behavior.

[19]  R. Duman,et al.  Regulation of BDNF and trkB mRNA in rat brain by chronic electroconvulsive seizure and antidepressant drug treatments , 1995, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[20]  M. Papp,et al.  Antidepressant-like effects of 1-aminocyclopropanecarboxylic acid and D-cycloserine in an animal model of depression. , 1996, European journal of pharmacology.

[21]  Bita Moghaddam,et al.  Activation of Glutamatergic Neurotransmission by Ketamine: A Novel Step in the Pathway from NMDA Receptor Blockade to Dopaminergic and Cognitive Disruptions Associated with the Prefrontal Cortex , 1997, The Journal of Neuroscience.

[22]  E. Przegaliński,et al.  Antidepressant-like Effects of a Partial Agonist at Strychnine-insensitive Glycine Receptors and a Competitive NMDA Receptor Antagonist , 1997, Neuropharmacology.

[23]  G. Ossowska,et al.  The effect of NMDA antagonists on footshock-induced fighting behavior in chronically stressed rats. , 1997, Journal of Physiology and Pharmacology.

[24]  A. Pałucha,et al.  Antidepressant treatment influences group I of glutamate metabotropic receptors in slices from hippocampal CA1 region. , 1998, European journal of pharmacology.

[25]  G. Brooker,et al.  Brain-Derived Neurotrophic Factor and Basic Fibroblast Growth Factor Downregulate NMDA Receptor Function in Cerebellar Granule Cells , 1998, The Journal of Neuroscience.

[26]  P. Skolnick,et al.  Adaptation of cortical NMDA receptors by chronic treatment with specific serotonin reuptake inhibitors. , 1998, European journal of pharmacology.

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

[28]  P. Skolnick,et al.  Antidepressants for the new millennium. , 1999, European journal of pharmacology.

[29]  M. Bijak,et al.  An antidepressant-induced decrease in the responsiveness of hippocampal neurons to group I metabotropic glutamate receptor activation. , 1999, European journal of pharmacology.

[30]  G F Mason,et al.  Reduced cortical gamma-aminobutyric acid levels in depressed patients determined by proton magnetic resonance spectroscopy. , 1999, Archives of general psychiatry.

[31]  G Lynch,et al.  Positive Modulation of AMPA Receptors Increases Neurotrophin Expression by Hippocampal and Cortical Neurons , 2000, The Journal of Neuroscience.

[32]  Y. Smith,et al.  Activation of Metabotropic Glutamate Receptor 5 Has Direct Excitatory Effects and Potentiates NMDA Receptor Currents in Neurons of the Subthalamic Nucleus , 2000, The Journal of Neuroscience.

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

[34]  T. Saijo,et al.  [Proton magnetic resonance spectroscopy of the autistic brain]. , 2001, No to hattatsu = Brain and development.

[35]  P. Skolnick,et al.  Antidepressant-like actions of an AMPA receptor potentiator (LY392098) , 2001, Neuropharmacology.

[36]  G. Nowak,et al.  Antidepressant-like properties of zinc in rodent forced swim test , 2001, Brain Research Bulletin.

[37]  Pharmacological validation of the chronic mild stress model of depression , 2001, European Neuropsychopharmacology.

[38]  A. Gingras,et al.  A rapamycin-sensitive signaling pathway contributes to long-term synaptic plasticity in the hippocampus , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[39]  H. Schild,et al.  Proton magnetic resonance spectroscopy of the motor cortex in 70 patients with amyotrophic lateral sclerosis. , 2001, Archives of neurology.

[40]  P. Skolnick,et al.  Regulation of BDNF expression in primary neuron culture by LY392098, a novel AMPA receptor potentiator , 2001, Neuropharmacology.

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

[42]  David Bleakman,et al.  An AMPA receptor potentiator modulates hippocampal expression of BDNF: an in vivo study , 2002, Neuropharmacology.

[43]  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.

[44]  H. Manji,et al.  Modulators of the glutamatergic system: implications for the development of improved therapeutics in mood disorders. , 2002, Psychopharmacology bulletin.

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

[46]  H. Scheich,et al.  Rapamycin‐sensitive signalling in long‐term consolidation of auditory cortex‐dependent memory , 2003, The European journal of neuroscience.

[47]  M. Bergeron,et al.  Chronic AMPA receptor potentiator (LY451646) treatment increases cell proliferation in adult rat hippocampus , 2003, Neuropharmacology.

[48]  P. Sanna,et al.  Time-restricted role for dendritic activation of the mTOR-p70S6K pathway in the induction of late-phase long-term potentiation in the CA1 , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[49]  Eric Klann,et al.  Activation of the Phosphoinositide 3-kinase–akt–mammalian Target of Rapamycin Signaling Pathway Is Required for Metabotropic Glutamate Receptor-dependent Long-term Depression , 2022 .

[50]  John H Krystal,et al.  Subtype-specific alterations of gamma-aminobutyric acid and glutamate in patients with major depression. , 2004, Archives of general psychiatry.

[51]  P. Matthews,et al.  Increased brain GABA concentrations following acute administration of a selective serotonin reuptake inhibitor. , 2004, The American journal of psychiatry.

[52]  Sylvain Houle,et al.  Serotonin transporter occupancy of five selective serotonin reuptake inhibitors at different doses: an [11C]DASB positron emission tomography study. , 2004, The American journal of psychiatry.

[53]  J. Cryan,et al.  Don't worry 'B' happy!: a role for GABA(B) receptors in anxiety and depression. , 2005, Trends in pharmacological sciences.

[54]  Gregor Hasler,et al.  Normal Prefrontal Gamma-Aminobutyric Acid Levels in Remitted Depressed Subjects Determined by Proton Magnetic Resonance Spectroscopy , 2005, Biological Psychiatry.

[55]  P. Serrano,et al.  Protein synthesis‐dependent LTP in isolated dendrites of CA1 pyramidal cells , 2005, Hippocampus.

[56]  P. Renshaw,et al.  Prefrontal GABA levels in cocaine-dependent subjects increase with pramipexole and venlafaxine treatment , 2005, Psychopharmacology.

[57]  G. Nowak,et al.  GABAergic hypotheses of anxiety and depression: focus on GABA-B receptors. , 2005, Drugs of today.

[58]  B. Szewczyk,et al.  Potential antidepressant-like effect of MTEP, a potent and highly selective mGluR5 antagonist , 2005, Pharmacology Biochemistry and Behavior.

[59]  J. Avruch,et al.  Glutamatergic Regulation of the p70S6 Kinase in Primary Mouse Neurons* , 2005, Journal of Biological Chemistry.

[60]  Perry F. Renshaw,et al.  Prefrontal GABA levels in cocaine-dependent subjects increase with pramipexole and venlafaxine treatment , 2005, Psychopharmacology.

[61]  J. Lauriello,et al.  Effects of ketamine on anterior cingulate glutamate metabolism in healthy humans: a 4-T proton MRS study. , 2005, The American journal of psychiatry.

[62]  J. Bukszár,et al.  Association between glutamic acid decarboxylase genes and anxiety disorders, major depression, and neuroticism , 2006, Molecular Psychiatry.

[63]  Paul J Carlson,et al.  A randomized trial of an N-methyl-D-aspartate antagonist in treatment-resistant major depression. , 2006, Archives of general psychiatry.

[64]  S. Marenco,et al.  Correction of frequency and phase variations induced by eddy currents in localized spectroscopy with multiple echo times , 2007, Magnetic resonance in medicine.

[65]  Gregor Hasler,et al.  Reduced prefrontal glutamate/glutamine and gamma-aminobutyric acid levels in major depression determined using proton magnetic resonance spectroscopy. , 2007, Archives of general psychiatry.

[66]  G. Sanacora,et al.  GABAergic contributions to the pathophysiology of depression and the mechanism of antidepressant action. , 2007, CNS & neurological disorders drug targets.

[67]  B. Moghaddam,et al.  NMDA Receptor Hypofunction Produces Opposite Effects on Prefrontal Cortex Interneurons and Pyramidal Neurons , 2007, The Journal of Neuroscience.

[68]  Guang Chen,et al.  Cellular Mechanisms Underlying the Antidepressant Effects of Ketamine: Role of α-Amino-3-Hydroxy-5-Methylisoxazole-4-Propionic Acid Receptors , 2008, Biological Psychiatry.

[69]  David Bonekamp,et al.  Regional apparent metabolite concentrations in young adult brain measured by 1H MR spectroscopy at 3 Tesla , 2008, Journal of magnetic resonance imaging : JMRI.

[70]  W. Bunney,et al.  Global Brain Gene Expression Analysis Links Glutamatergic and GABAergic Alterations to Suicide and Major Depression , 2009, PloS one.

[71]  F. Holsboer,et al.  Polymorphisms in the GAD2 gene‐region are associated with susceptibility for unipolar depression and with a risk factor for anxiety disorders , 2009, American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics.

[72]  N. deSouza,et al.  Epithelial and stromal metabolite changes in the transition from cervical intraepithelial neoplasia to cervical cancer: an in vivo 1H magnetic resonance spectroscopic imaging study with ex vivo correlation , 2009, European Radiology.

[73]  J. Soares,et al.  Normal metabolite levels in the left dorsolateral prefrontal cortex of unmedicated major depressive disorder patients: A single voxel 1H spectroscopy study , 2009, Psychiatry Research: Neuroimaging.

[74]  Shang-Yueh Tsai,et al.  Quantification of non–water‐suppressed MR spectra with correction for motion‐induced signal reduction , 2009, Magnetic resonance in medicine.

[75]  W. Shaikh,et al.  Magnesium intake and depression. , 2009 .

[76]  K. Wilson,et al.  Magnesium intake and depression. , 2009, The Australian and New Zealand journal of psychiatry.

[77]  Dennis S. Charney,et al.  Amino Acid Neurotransmitters Assessed by Proton Magnetic Resonance Spectroscopy: Relationship to Treatment Resistance in Major Depressive Disorder , 2009, Biological Psychiatry.

[78]  G. Sanacora.  Cortical Inhibition, Gamma-Aminobutyric Acid, and Major Depression: There Is Plenty of Smoke but Is There Fire? , 2010, Biological Psychiatry.

[79]  A. Jasiński,et al.  Metabolic changes in rat brain following intracerebroventricular injections of streptozotocin: a model of sporadic Alzheimer's disease. , 2010, Acta neurochirurgica. Supplement.

[80]  G. Rajkowska,et al.  Reduced Density of Calbindin Immunoreactive GABAergic Neurons in the Occipital Cortex in Major Depression: Relevance to Neuroimaging Studies , 2010, Biological Psychiatry.

[81]  Georg Northoff,et al.  Is subcortical–cortical midline activity in depression mediated by glutamate and GABA? A cross-species translational approach , 2010, Neuroscience & Biobehavioral Reviews.

[82]  Paul B. Fitzgerald,et al.  Evidence of Cortical Inhibitory Deficits in Major Depressive Disorder , 2010, Biological Psychiatry.

[83]  Nanxin Li,et al.  mTOR-Dependent Synapse Formation Underlies the Rapid Antidepressant Effects of NMDA Antagonists , 2010, Science.

[84]  M. Oudkerk,et al.  The added value of quantitative multi-voxel MR spectroscopy in breast magnetic resonance imaging , 2011, European Radiology.

[85]  S. Chaki,et al.  Involvement of AMPA receptor in both the rapid and sustained antidepressant-like effects of ketamine in animal models of depression , 2011, Behavioural Brain Research.

[86]  M. Austin,et al.  The mTOR signaling pathway in the prefrontal cortex is compromised in major depressive disorder , 2011, Progress in Neuro-Psychopharmacology and Biological Psychiatry.

[87]  J. Krystal,et al.  The antidepressant effect of ketamine is not associated with changes in occipital amino acid neurotransmitter content as measured by [1H]-MRS , 2011, Psychiatry Research: Neuroimaging.

[88]  K. Behar,et al.  1H-[13C]-Nuclear Magnetic Resonance Spectroscopy Measures of Ketamine's Effect on Amino Acid Neurotransmitter Metabolism , 2012, Biological Psychiatry.

[89]  D. Price,et al.  Basic neurochemistry : principles of molecular, cellular and medical neurobiology , 2012 .

[90]  G. Barker,et al.  Ketamine effects on brain GABA and glutamate levels with 1H-MRS: relationship to ketamine-induced psychopathology , 2012, Molecular Psychiatry.

[91]  P. Cowen,et al.  Lack of effect of ketamine on cortical glutamate and glutamine in healthy volunteers: a proton magnetic resonance spectroscopy study , 2012, Journal of psychopharmacology.

[92]  J. John Mann,et al.  ‘ Glx ’ Measured by J-editing / MEGA-PRESS is Primarily ‘ Pure ’ Glutamate ... Or is it ? , 2012 .

[93]  Victoria Arango,et al.  Neuron density and serotonin receptor binding in prefrontal cortex in suicide. , 2012, The international journal of neuropsychopharmacology.

[94]  M. Martínez-González,et al.  Magnesium intake is not related to depression risk in Spanish university graduates. , 2012, The Journal of nutrition.

[95]  H. Murck.  Ketamine, magnesium and major depression--from pharmacology to pathophysiology and back. , 2013, Journal of psychiatric research.

[96]  M. Boldrini,et al.  Hippocampal Granule Neuron Number and Dentate Gyrus Volume in Antidepressant-Treated and Untreated Major Depression , 2013, Neuropsychopharmacology.

[97]  S. Mathew,et al.  Clinical Handbook for the Management of Mood Disorders: Ketamine in treatment-resistant depression , 2013 .

[98]  Hsiao-Wen Chung,et al.  Quantitative comparison of post‐processing methods for reduction of frequency modulation sidebands in non‐water suppression 1H MRS , 2013, NMR in biomedicine.

[99]  R. Parsey,et al.  Clinical Handbook for the Management of Mood Disorders: Brain imaging , 2013 .

[100]  M. Martínez-González,et al.  Magnesium and depression: a systematic review , 2013, Nutritional neuroscience.

[101]  M. Kabbaj,et al.  Sex differences in the antidepressant-like effects of ketamine , 2013, Neuropharmacology.

[102]  Dennis S. Charney,et al.  Rapid and Longer-Term Antidepressant Effects of Repeated Ketamine Infusions in Treatment-Resistant Major Depression , 2013, Biological Psychiatry.

[103]  M. Kuskowski,et al.  Augmentation of response and remission to serial intravenous subanesthetic ketamine in treatment resistant depression. , 2014, Journal of affective disorders.

[104]  M. Leboyer,et al.  Ketamine administration in depressive disorders: a systematic review and meta-analysis , 2014, Psychopharmacology.

[105]  R. Lam,et al.  A systematic review and meta-analysis of randomized, double-blind, placebo-controlled trials of ketamine in the rapid treatment of major depressive episodes , 2014, Psychological Medicine.

[106]  W. Drevets,et al.  Neural correlates of rapid antidepressant response to ketamine in bipolar disorder , 2014, Bipolar disorders.

[107]  Zhengchao Dong,et al.  Proton MRS and MRSI of the brain without water suppression. , 2015, Progress in nuclear magnetic resonance spectroscopy.

[108]  C. Zarate,et al.  Ketamine for Treatment-Resistant Depression , 2016 .