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

2010; Elsevier BV; Volume: 68; Issue: 9 Linguagem: Inglês

10.1016/j.biopsych.2010.06.016

ISSN

1873-2402

Autores

Çağrı Yüksel, Döst Öngür,

Tópico(s)

Advanced NMR Techniques and Applications

Resumo

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. 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. Mood disorders are common and disabling psychiatric illnesses that affect individuals worldwide and cause significant negative impact on public health (1Kessler R.C. Berglund P. Demler O. Jin R. Merikangas K.R. Walters E.E. 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Although gross disruptions in glutamatergic transmission are associated with major neurologic abnormalities (e.g., seizure disorders), more subtle abnormalities are likely in psychiatric disorders. In addition to the currently used agents with glutamatergic effects (e.g., lamotrigine), therapies targeting this neurotransmitter system are under development and hold promise as alternatives to current mood disorder treatments (8Skolnick P. Popik P. Trullas R. Glutamate-based antidepressants: 20 Years on.Trends Pharmacol Sci. 2009; 30: 563-569Abstract Full Text Full Text PDF PubMed Scopus (346) Google Scholar, 9Sanacora G. Zarate C.A. Krystal J.H. Manji H.K. Targeting the glutamatergic system to develop novel, improved therapeutics for mood disorders.Nat Rev Drug Discov. 2008; 7: 426-437Crossref PubMed Scopus (722) Google Scholar, 10Krystal J.H. Sanacora G. Blumberg H. Anand A. Charney D.S. Marek G. et al.Glutamate and GABA systems as targets for novel antidepressant and mood-stabilizing treatments.Mol Psychiatry. 2002; 7: S71-S80Crossref PubMed Scopus (474) Google Scholar). Proton magnetic resonance spectroscopy (1H MRS) is a noninvasive neuroimaging technique that allows in vivo quantification of metabolites, including those related to glutamate, in localized brain regions. Depending on field strength and signal-to-noise ratio, glutamate-related metabolites (especially glutamate and glutamine) can be quantified either separately or as a composite of glutamate, glutamine, gamma-amino butyric acid (GABA), and other metabolites (termed Glx) in the central nervous system. In the past decade, studies using 1H MRS in mood disorders have reported abnormalities in glutamate-related metabolites in diverse brain regions. In this review, we first provide a framework for understanding the role of glutamate and glutamine in neurotransmission and briefly examine the evidence implicating these metabolites in mood disorders. Next, we focus on 1H MRS studies of glutamate-related metabolites in mood disorders and discuss the implications of these findings for pathophysiology. 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 (11Erecinska M. Silver I.A. Metabolism and role of glutamate in mammalian brain.Prog Neurobiol. 1990; 35: 245-296Crossref PubMed Scopus (601) Google Scholar, 12Bak L.K. Schousboe A. Waagepetersen H.S. The glutamate/GABA-glutamine cycle: Aspects of transport, neurotransmitter homeostasis and ammonia transfer.J Neurochem. 2006; 98: 641-653Crossref PubMed Scopus (767) Google Scholar). 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Lamotrigine in the treatment of bipolar disorder.Expert Opin Pharmacother. 2005; 6: 1401-1408Crossref PubMed Scopus (20) Google Scholar), and as adjunct in bipolar and unipolar depression (24Gutierrez R.L. McKercher R.M. Galea J. Jamison K.L. Lamotrigine augmentation strategy for patients with treatment-resistant depression.CNS Spectr. 2005; 10: 800-805PubMed Google Scholar, 25Nierenberg A.A. Ostacher M.J. Calabrese J.R. Ketter T.A. Marangell L.B. Miklowitz D.J. et al.Treatment-resistant bipolar depression: A STEP-BD equipoise randomized effectiveness trial of antidepressant augmentation with lamotrigine, inositol, or risperidone.Am J Psychiatry. 2006; 163: 210-216Crossref PubMed Scopus (225) Google Scholar). Another antiglutamatergic agent, riluzole, is effective as an add on and as monotherapy for treatment-resistant depression and in combination therapy for bipolar depression in open-label studies (26Sanacora G. Kendell S.F. Fenton L. Coric V. Krystal J.H. 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Increased levels of glutamate in brains from patients with mood disorders.Biol Psychiatry. 2007; 62: 1310-1316Abstract Full Text Full Text PDF PubMed Scopus (500) Google Scholar). Thus, these studies were not conclusive for the direction of glutamate changes in mood disorders. In postmortem studies, glial cell number and density reduction is consistently demonstrated in mood disorders in the subgenual prefrontal cortex (47Ongur D. Drevets W.C. Price J.L. Glial reduction in the subgenual prefrontal cortex in mood disorders.Proc Natl Acad Sci U S A. 1998; 95: 13290-13295Crossref PubMed Scopus (1298) Google Scholar), orbitofrontal cortex (48Rajkowska G. Miguel-Hidalgo J.J. Wei J. Dilley G. Pittman S.D. Meltzer H.Y. et al.Morphometric evidence for neuronal and glial prefrontal cell pathology in major depression.Biol Psychiatry. 1999; 45: 1085-1098Abstract Full Text Full Text PDF PubMed Scopus (1268) Google Scholar), supracallosal anterior cingulate cortex (49Cotter D.R. Pariante C.M. 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Furthermore, expression of glial glutamate transporters EAAT1 and EAAT2 and the glia-specific enzyme glutamine synthetase is reduced in dorsolateral prefrontal cortex (DLPFC) and anterior cingulate cortex (ACC) of individuals with major depression (53Choudary P.V. Molnar M. Evans S.J. Tomita H. Li J.Z. Vawter M.P. et al.Altered cortical glutamatergic and GABAergic signal transmission with glial involvement in depression.Proc Natl Acad Sci U S A. 2005; 102: 15653-15658Crossref PubMed Scopus (552) Google Scholar). Finally, postmortem studies of mood disorders also report abnormalities in expression of NMDA (54Beneyto M. Meador-Woodruff J.H. Lamina-specific abnormalities of NMDA receptor-associated postsynaptic protein transcripts in the prefrontal cortex in schizophrenia and bipolar disorder.Neuropsychopharmacology. 2008; 33: 2175-2186Crossref PubMed Scopus (212) Google Scholar, 55Law A.J. Deakin J.F. 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Lamina-specific abnormalities of AMPA receptor trafficking and signaling molecule transcripts in the prefrontal cortex in schizophrenia.Synapse. 2006; 60: 585-598Crossref PubMed Scopus (97) Google Scholar). Taken together, this literature suggests that glutamatergic abnormalities are a prominent feature of mood disorders. In vivo 1H MRS studies of glutamate-related metabolites provide an additional window into glutamatergic abnormalities in mood disorders, and we argue that these studies may provide information about pathophysiology in these conditions. 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 subjects aged younger than 18 years were excluded. We considered a meta-analytic approach but concluded this was not justified given the substantial differences in MRS outcome measures, data acquisition, and data analysis among the studies included in this review. We note that many brain regions have been studied in MRS studies of mood disorders, with special emphasis on the cerebral cortex. We have summarized this literature without any classification of studies by brain region. Our rationale was that mood disorders are characterized by emotional, cognitive, psychomotor, and neurovegetative disturbances and it would not be surprising to find widespread alterations in multiple regions in these conditions. Indeed, we have found that the patterns of findings vary primarily by diagnosis and clinical state and not by brain region. By contrast, we cannot rule out differential regulation of glutamatergic neurotransmission by brain region, especially across cortical versus subcortical regions where synaptic arrangements are dramatically different. DSM-IV diagnosis was used in all studies except two MDD studies: Auer et al. (60Auer D.P. Putz B. Kraft E. Lipinski B. Schill J. Holsboer F. Reduced glutamate in the anterior cingulate cortex in depression: An in vivo proton magnetic resonance spectroscopy study.Biol Psychiatry. 2000; 47: 305-313Abstract Full Text Full Text PDF PubMed Scopus (484) Google Scholar) re cruited patients with ICD-10 MDD, and Walter et al. (61Walter M. Henning A. Grimm S. Schulte R.F. Beck J. Dydak U. et al.The relationship between aberrant neuronal activation in the pregenual anterior cingulate, altered glutamatergic metabolism, and anhedonia in major depression.Arch Gen Psychiatry. 2009; 66: 478-486Crossref PubMed Scopus (253) Google Scholar) 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 (61Walter M. Henning A. Grimm S. Schulte R.F. Beck J. Dydak U. et al.The relationship between aberrant neuronal activation in the pregenual anterior cingulate, altered glutamatergic metabolism, and anhedonia in major depression.Arch Gen Psychiatry. 2009; 66: 478-486Crossref PubMed Scopus (253) Google Scholar, 62Binesh N. Kumar A. Hwang S. Mintz J. Thomas M.A. Neurochemistry of late-life major depression: A pilot two-dimensional MR spectroscopic study.J Magn Reson Imaging. 2004; 20: 1039-1045Crossref PubMed Scopus (59) Google Scholar). We identified 11 studies that quantified glutamate-related metabolites (Glx, glutamate, glutamine) in patients with MDD and two studies in individuals with a history of MDD (Table 1). In the depressive state, all the studies except two (61Walter M. Henning A. Grimm S. Schulte R.F. Beck J. Dydak U. et al.The relationship between aberrant neuronal activation in the pregenual anterior cingulate, altered glutamatergic metabolism, and anhedonia in major depression.Arch Gen Psychiatry. 2009; 66: 478-486Crossref PubMed Scopus (253) Google Scholar, 63Sanacora G. Gueorguieva R. Epperson C.N. Wu Y.T. Appel M. Rothman D.L. et al.Subtype-specific alterations of gamma-aminobutyric acid and glutamate in patients with major depression.Arch Gen Psychiatry. 2004; 61: 705-713Crossref PubMed Scopus (700) Google Scholar) reported on Glx levels, and most found a reduction of this measure in several brain regions. Glx was reported to be reduced in the ACC (60Auer D.P. Putz B. Kraft E. Lipinski B. Schill J. Holsboer F. Reduced glutamate in the anterior cingulate cortex in depression: An in vivo proton magnetic resonance spectroscopy study.Biol Psychiatry. 2000; 47: 305-313Abstract Full Text Full Text PDF PubMed Scopus (484) Google Scholar, 64Pfleiderer B. Michael N. Erfurth A. Ohrmann P. Hohmann U. Wolgast M. et al.Effective electroconvulsive therapy reverses glutamate/glutamine deficit in the left anterior cingulum of unipolar depressed pat

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