Magnetic Resonance Spectroscopy Studies of Glutamate-Related Abnormalities in Mood Disorders

doi:10.1016/j.biopsych.2010.06.016

Biological Psychiatry

Volume 68, Issue 9, 1 November 2010, Pages 785-794

https://doi.org/10.1016/j.biopsych.2010.06.016 Get rights and content

In mood disorders, there is growing evidence for glutamatergic abnormalities derived from peripheral measures of glutamatergic metabolites in patients, postmortem studies on glutamate-related markers, and animal studies on the mechanism of action of available treatments. Magnetic resonance spectroscopy (MRS) has the potential to corroborate and extend these findings with the advantage of in vivo assessment of glutamate-related metabolites in different disease states, in response to treatment, and in relation with functional imaging data. In this article, we first review the biological significance of glutamate, glutamine, and Glx (composed mainly of glutamate and glutamine). Next, we review the MRS literature in mood disorders, examining these glutamate-related metabolites. Here, we find a highly consistent pattern of Glx-level reductions in major depressive disorder and elevations in bipolar disorder. In addition, studies of depression, regardless of diagnosis, provide suggestive evidence for reduced glutamine/glutamate ratio and in mania for elevated glutamine/glutamate ratio. These patterns suggest that the glutamate-related metabolite pool (not all of it necessarily relevant to neurotransmission) is constricted in major depressive disorder and expanded in bipolar disorder. Depressive and manic episodes may be characterized by modulation of the glutamine/glutamate ratio in opposite directions, possibly suggesting reduced versus elevated glutamate conversion to glutamine by glial cells, respectively. We discuss the implications of these results for the pathophysiology of mood disorders and suggest future directions for MRS studies.

Section snippets

Glutamate Neurotransmission and Recycling

Glutamate is the most abundant neurotransmitter in the brain, as well as a structural component of proteins, a component of intermediary energy metabolism, and a precursor for glutamine, GABA, and glutathione (11, 12).

Following its release to the synaptic cleft, glutamate is taken up by adjacent cells through excitatory amino acid transporters (EAAT). Astrocytes are responsible for uptake of most extracellular glutamate via EAAT1 (GLAST) and EAAT2 (GLT1) (12, 13). Astrocytes maintain

Glutamate and Mood Disorders

The glutamatergic system was first implicated in mood disorders when D-cycloserine, a partial agonist at the N-methyl-D-aspartate (NMDA) receptor glycine site and an antagonist at higher doses, showed antidepressant-like properties (20). Several other medications with glutamatergic activity have since been studied for their antidepressant properties. Ketamine, a noncompetitive NMDA antagonist, showed antidepressant effects after a single-dose intravenous infusion in two double-blind,

Methods and Materials

Articles were identified on PubMed (http://www.ncbi.nlm.nih.gov/pubmed) using key words “¹H magnetic resonance spectroscopy,” “mood disorder,” “bipolar disorder,” “major depression,” “glutamate,” “glutamine,” and “Glx.” Included studies met the following criteria: published in English; compared metabolites in BD or MDD with normal controls; quantified Glx, glutamate, and/or glutamine; and included adult subjects. Studies on children and adolescents or those including a substantial number of

Diagnostic Assessments

DSM-IV diagnosis was used in all studies except two MDD studies: Auer et al. (60) re cruited patients with ICD-10 MDD, and Walter et al. (61) did not report diagnostic criteria. Diagnoses were ascertained by structured interviews in most of the studies using the Structured Clinical Interview for DSM-IV (SCID-IV) or Munich checklist for DSM-IV diagnoses. Diagnostic method was not reported in two studies (61, 62).

Major Depressive Disorder

We identified 11 studies that quantified glutamate-related metabolites (Glx,

Discussion

There is a large and compelling literature on glutamatergic abnormalities in mood disorders, consisting of peripheral glutamate and related metabolite measures, postmortem markers related to glutamatergic neurotransmission, and insights into mechanisms of action of psychotropic agents. Proton MRS studies are crucial in this field because they provide noninvasive, in vivo assessments of glutamatergic function. The sophistication and utility of proton MRS studies has been improving in recent

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ReviewMagnetic Resonance Spectroscopy Studies of Glutamate-Related Abnormalities in Mood Disorders

Section snippets

Glutamate Neurotransmission and Recycling

Glutamate and Mood Disorders

Methods and Materials

Diagnostic Assessments

Major Depressive Disorder

Discussion

J. J Affect Disord

Trends Pharmacol Sci

Prog Neurobiol

Neurochem Int

Trends Neurosci

Biochem Pharmacol

Biol Psychiatry

Biol Psychiatry

Biol Psychiatry

Biol Psychiatry

Neuroscience

Eur Neuropsychopharmacol

Biol Psychiatry

Biol Psychiatry

Brain Res

Biol Psychiatry

Biol Psychiatry

Brain Res Bull

Biol Psychiatry

Biol Psychiatry

Biol Psychiatry

Brain Res

Brain Res Bull

Biol Psychiatry

Psychiatry Res

Neuroimage

Biol Psychiatry

Biol Psychiatry

Biol Psychiatry

Psychiatry Res

Psychiatry Res

Psychiatry Res

Brain Res

Neuroimage

Lifetime prevalence and age-of-onset distributions of DSM-IV disorders in the national comorbidity survey replication

Arch Gen Psychiatry

The burden of depression and anxiety in general medicine

J Clin Psychiatry

The long-term natural history of the weekly symptomatic status of bipolar I disorder

Arch Gen Psychiatry

Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: A STAR*D report

Am J Psychiatry

Beyond monoamines: Glutamatergic function in mood disorders

CNS Spectr

Targeting the glutamatergic system to develop novel, improved therapeutics for mood disorders

Nat Rev Drug Discov

Glutamate and GABA systems as targets for novel antidepressant and mood-stabilizing treatments

Mol Psychiatry

The glutamate/GABA-glutamine cycle: Aspects of transport, neurotransmitter homeostasis and ammonia transfer

J Neurochem

Role of astrocytes in the maintenance and modulation of glutamatergic and GABAergic neurotransmission

Neurochem Res

Alteration of striatal glutamate release after glutamine synthetase inhibition

J Neurochem

Role of glial cells for the basal and Ca2+-dependent K+-evoked release of transmitter amino acids investigated by microdialysis

J Neurochem

Altered prefrontal glutamate-glutamine-gamma-aminobutyric acid levels and relation to low cognitive performance and depressive symptoms in type 1 diabetes mellitus

Arch Gen Psychiatry

Cyloserine as an antidepressant agent

Am J Psychiatry

Review
Magnetic Resonance Spectroscopy Studies of Glutamate-Related Abnormalities in Mood Disorders