ReviewGlutamate and Gamma-Aminobutyric Acid Systems in the Pathophysiology of Major Depression and Antidepressant Response to Ketamine
Section snippets
Dysregulation of Glutamatergic and Gabaergic Neurotransmission in Depression
Proton MRS (1H-MRS) is an in vivo imaging technique for total tissue detection of neurochemicals, including N-acetylaspartate, GABA, Glu, glutamine (Gln), and a combination of Glu/Gln with a minor contribution from GABA (known as Glx) that is often reported owing to poor signal resolution between these metabolites in weaker magnetic fields. 1H-MRS studies examining levels of GABA, Glu, Gln, and Glx in the brain require an appreciation of Glu metabolism, particularly the Glu/Gln cycle (15, 16) (
Functional Circuitry Abnormalities in Depression
Neural circuitry describes the complex array of interconnected neurons in the brain from which simultaneous and coordinated information processing is refined and reorganized by experience-related synaptic changes (57). Neuroimaging methods that indirectly (e.g., fMRI blood–oxygen level dependent [BOLD] signal) or directly (e.g., EEG and MEG) examine neural activity aim to identify circuitry-level abnormalities and/or response to behavioral or neurochemical interventions (17). Considerations are
Ketamine in Depression
Ketamine’s antidepressant effects were demonstrated over a decade ago in a double-blind, placebo-controlled clinical study of eight depressed patients randomly assigned to receive either a subanesthetic dose (0.5 mg/kg intravenously over 40 minutes) of ketamine or saline. Four of the eight patients (n = 7 completers) had an antidepressant response to ketamine (defined as a reduction of 50% or greater on the Hamilton Depression Rating Scale) (10). Subsequently, our group and others replicated
Antidepressant Response to Ketamine and Glu/Gaba Neurotransmission
To date, five 1H-MRS studies have examined Glu, Gln, Glx, and/or GABA levels, and one PET study used a mGluR5 ligand before and after intravenous ketamine infusion; all were conducted in healthy subjects (87, 88, 89, 90) (Table 1). In a double-blind, placebo-controlled, crossover study of 10 men (n = 8 completers), elevated Gln levels were observed in the ACC 2 hours after infusion, correlating with psychotomimetic symptoms (87). In an open-label study of 13 men, significantly elevated Glu
Ketamine and Functional Neural Circuitry in Depression
Increased pretreatment neural activity in the rostral ACC associates with antidepressant response across different pharmacologic, electrophysiological, and behavioral interventions (74), suggesting that a common neurobiological signature may be associated with antidepressant response to treatment. In healthy subjects, functional connectivity between the rostral ACC and mPFC increased acutely (95) and decreased 24 hours after ketamine infusion (96). Furthermore, with the use of PET imaging
Ketamine As A Functional Neurocircuitry Modulator: Future Directions
In depressed patients, evidence from neurochemical studies of MDD and BD suggests that alterations in Glu-related excitatory neurotransmission exist in a subset of patients. Although evidence of isolated abnormalities in GABA-related inhibitory neurotransmission in depression has been less clear, a reduction in efficient energy metabolism in glutamatergic neurons may lead to an imbalance of Glu over GABA neurotransmission that manifests as network connectivity perturbations in BD and MDD.
Acknowledgments and Disclosures
This work was supported by the Intramural Research Program at the National Institute of Mental Health, National Institutes of Health (Grant Nos. IRP-NIMH-NIH and ZIA MH002857).
We thank the 7SE research unit and staff for their support, and Ms. Ioline Henter for invaluable editorial assistance.
MSL, MJN, EDB, MP, LTP, and AN report no biomedical financial interests or potential conflicts of interest. CAZ is listed as a co-inventor on a patent application for the use of ketamine and its
References (122)
- et al.
Functional antagonists at the NMDA receptor complex exhibit antidepressant actions
Eur J Pharmacol
(1990) - et al.
Cellular mechanisms underlying the antidepressant effects of ketamine: Role of alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptors
Biol Psychiatry
(2008) - et al.
Stress, glucocorticoids and glutamate release: Effects of antidepressant drugs
Neurochem Int
(2011) - et al.
Towards a glutamate hypothesis of depression: an emerging frontier of neuropsychopharmacology for mood disorders
Neuropharmacology
(2012) - et al.
Antidepressant effects of ketamine in depressed patients
Biol Psychiatry
(2000) - et al.
Magnetic resonance spectroscopy studies of glutamate-related abnormalities in mood disorders
Biol Psychiatry
(2010) - et al.
Indirect evidence of selective glial involvement in glutamate-based mechanisms of mood regulation in depression: Meta-analysis of absolute prefrontal neuro-metabolic concentrations
Eur Neuropsychopharmacol
(2015) - et al.
A systematic review and meta-analysis of proton magnetic resonance spectroscopy and mismatch negativity in bipolar disorder
Eur Neuropsychopharmacol
(2013) - et al.
Alterations of cerebral glutamate in the euthymic state of patients with bipolar disorder
Psychiatry Res
(2015) - et al.
Review of 1H magnetic resonance spectroscopy findings in major depressive disorder: A meta-analysis
Psychiatry Res
(2006)
Reduced glutamate in the anterior cingulate cortex in depression: An in vivo proton magnetic resonance spectroscopy study
Biol Psychiatry
Increased choline-containing compounds in the orbitofrontal cortex and hippocampus in euthymic patients with bipolar disorder: A proton magnetic resonance spectroscopy study
Psychiatry Res
Metabolic alterations in medication-free patients with bipolar disorder: A 3T CSF-corrected magnetic resonance spectroscopic imaging study
Psychiatry Res
Brain GABA levels in patients with bipolar disorder
Prog Neuropsychopharmacol Biol Psychiatry
Amino acid neurotransmitters assessed by proton magnetic resonance spectroscopy: Relationship to treatment resistance in major depressive disorder
Biol Psychiatry
Magnetic resonance spectroscopy studies of the glutamatergic system in mood disorders: A pathway to diagnosis, novel therapeutics, and personalized medicine?
Biol Psychiatry
Potential antidepressant-like effect of MTEP, a potent and highly selective mGluR5 antagonist
Pharmacol Biochem Behav
Preclinical evaluation of [(18)F]PK-209, a new PET ligand for imaging the ion-channel site of NMDA receptors
Nucl Med Biol
Normal prefrontal gamma-aminobutyric acid levels in remitted depressed subjects determined by proton magnetic resonance spectroscopy
Biol Psychiatry
Anterior cingulate Glutamate-Glutamine cycle metabolites are altered in euthymic bipolar I disorder
Eur Neuropsychopharmacol
Exploratory analysis for a targeted patient population responsive to the metabotropic glutamate 2/3 receptor agonist pomaglumetad methionil in schizophrenia
Biol Psychiatry
Demonstration of useful differences between magnetoencephalogram and electroencephalogram
Electroencephalogr Clin Neurophysiol
Magnetoencephalography: Applications in psychiatry
Biol Psychiatry
Resting-state functional connectivity in major depression: Abnormally increased contributions from subgenual cingulate cortex and thalamus
Biol Psychiatry
Is subcortical-cortical midline activity in depression mediated by glutamate and GABA? A cross-species translational approach
Neurosci Biobehav Rev
Neural circuits underlying the pathophysiology of mood disorders
Trends Cogn Sci
A systematic literature review of resting state network--Functional MRI in bipolar disorder
J Affect Disord
Resting-state functional network connectivity in prefrontal regions differs between unmedicated patients with bipolar and major depressive disorders
J Affect Disord
Task induced modulation of neural oscillations in electrophysiological brain networks
Neuroimage
Group differences in MEG-ICA derived resting state networks: Application to major depressive disorder
Neuroimage
Dynamic functional connectivity: Promise, issues, and interpretations
Neuroimage
Glutamate N-methyl-D-aspartate receptor antagonists rapidly reverse behavioral and synaptic deficits caused by chronic stress exposure
Biol Psychiatry
In vivo ketamine-induced changes in [(11)C]ABP688 binding to metabotropic glutamate receptor subtype 5
Biol Psychiatry
The antidepressant effect of ketamine is not associated with changes in occipital amino acid neurotransmitter content as measured by [(1)H]-MRS
Psychiatry Res
Neural correlates of rapid antidepressant response to ketamine in treatment-resistant unipolar depression: A preliminary positron emission tomography study
Biol Psychiatry
Adaptation of N-methyl-D-aspartate (NMDA) receptors following antidepressant treatment: Implications for the pharmacotherapy of depression
Pharmacopsychiatry
Adaptive changes in the N-methyl-D-aspartate receptor complex after chronic treatment with imipramine and 1-aminocyclopropanecarboxylic acid
J Pharmacol Exp Ther
Ketamine: Teaching an old drug new tricks
Anesth Analg
Ketamine administration in depressive disorders: A systematic review and meta-analysis
Psychopharmacology (Berl)
Ketamine and other NMDA antagonists: Early clinical trials and possible mechanisms in depression
Am J Psychiatry
A randomized trial of an N-methyl-D-aspartate antagonist in treatment-resistant major depression
Arch Gen Psychiatry
Riluzole for relapse prevention following intravenous ketamine in treatment-resistant depression: A pilot randomized, placebo-controlled continuation trial
Int J Neuropsychopharmacol
Antidepressant efficacy of ketamine in treatment-resistant major depression: A two-site randomized controlled trial
Am J Psychiatry
The use of a series of ketamine infusions in two patients with treatment-resistant depression
J Neuropsychiatry Clin Neurosci
Glutamate and its receptors in the pathophysiology and treatment of major depressive disorder
J Neural Transm (Vienna)
The glutamate/GABA-glutamine cycle: Aspects of transport, neurotransmitter homeostasis and ammonia transfer
J Neurochem
In pursuit of neuroimaging biomarkers to guide treatment selection in major depressive disorder: A review of the literature
Ann N Y Acad Sci
Reduced prefrontal glutamate/glutamine and gamma-aminobutyric acid levels in major depression determined using proton magnetic resonance spectroscopy
Arch Gen Psychiatry
Subtype-specific alterations of gamma-aminobutyric acid and glutamate in patients with major depression
Arch Gen Psychiatry
Hippocampal abnormalities of glutamate/glutamine, N-acetylaspartate and choline in patients with depression are related to past illness burden
J Psychiatry Neurosci
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