Increased Anterior Cingulate/Medial Prefrontal Cortical Glutamate and Creatine in Bipolar Depression

UCLA Department of Psychiatry and Biobehavioral Sciences, Los Angeles, CA 55905, USA.
Neuropsychopharmacology (Impact Factor: 7.05). 01/2008; 32(12):2490-9. DOI: 10.1038/sj.npp.1301387
Source: PubMed


Proton magnetic resonance spectroscopy ((1)HMRS) is an in vivo brain imaging method that can be used to investigate psychotropic drug mechanism of action. This study evaluated baseline (1)HMRS spectra of bipolar depressed patients and whether the level of cerebral metabolites changed after an open trial of lamotrigine, an anti-glutamatergic mood stabilizer. Twenty-three bipolar depressed and 12 control subjects underwent a MRS scan of the anterior cingulate/medial prefrontal cortex. The scan was performed on a GE whole-body 1.5 T MRI scanner using single-voxel PRESS (TE/TR=30/3000 ms, 3 x 3 x 3 cm(3) and post-processed offline with LCModel. Baseline CSF-corrected absolute concentrations of glutamate+glutamine ([Glx]), glutamate ([Glu]), and creatine+phosphocreatine ([Cr]) were significantly higher in bipolar depressed subjects vs healthy controls. The non-melancholic subtype had significantly higher baseline [Glx] and [Glu] levels than the melancholic subtype. Remission with lamotrigine was associated with significantly lower post-treatment glutamine ([Gln]) in comparison to non-remission. These data suggest that non-melancholic bipolar depression is characterized by increased glutamate coupled with increased energy expenditure. Lamotrigine appears to reduce glutamine levels associated with treatment remission. Further study is encouraged to determine if these MR spectroscopic markers can delineate drug mechanism of action and subsequent treatment response.

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Available from: Jim Mintz, Aug 05, 2014
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    • "This suggests that different methodologies and the heterogeneity of BD may contribute to mixed findings. Previous 1 H-MRS studies have reported increased brain glutamate levels in the occipital cortex (Bhagwagar et al., 2007; Senaratne et al., 2009), the parieto-occipital cortex (Ongur et al., 2008), the hippocampus (HC) (Colla et al., 2009), the insula (Dager et al., 2004), the anterior cingulate cortex (ACC) (Frye et al., 2007; Ongur et al., 2008), and the left dorsolateral prefrontal cortex (Michael et al., 2009) of patients with BD, which may indicate increased glutamatergic neurotransmission or also changes in the cellular metabolism in these regions (Stork and Renshaw, 2005). It is suggested that the glutamate elevation in BD subjects represents a shift in energy redox state from oxidative phosphorylation toward glycolysis (Dager et al., 2004). "
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    ABSTRACT: There has been growing support for dysfunctions of the excitatory glutamatergic system and its implications for the psychophysiology of schizophrenia. However, previous studies reported mixed results regarding glutamate concentrations in schizophrenia with varying deviations across brain regions. We used an optimized proton magnetic resonance spectroscopy procedure to measure absolute glutamate concentrations in the left hippocampal region and the anterior cingulate cortex (ACC) in 29 medicated patients with schizophrenia and in 29 control participants without mental disorder. The glutamate concentrations were significantly lower in the ACC but higher in the hippocampus of patients compared to controls. ACC and hippocampal glutamate concentrations correlated positively in patients but not in controls. ACC glutamate was weakly associated with Clinical Global Impression score and duration of illness in patients. Glutamate concentrations in schizophrenia deviate from controls and show associations with disease severity. A higher concentration of hippocampal glutamate in schizophrenia compared to controls is shown. The association between ACC and hippocampus glutamate concentrations in patients with schizophrenia suggests an abnormal coupling of excitatory systems compared to controls as predicted by previous glutamate models of schizophrenia. © The Author 2015. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For permissions, please email:
    Full-text · Article · Sep 2015 · Schizophrenia Bulletin
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    • "The glutamatergic system has been also implicated in the pathophysiology and therapeutics of mood disorders (Machado-Vieira et al., 2012, 2009a). ACC studies in BD described altered glutamate (Glu) or glutamate+glutamine (Glx) levels during depressive and manic episodes (Frye et al., 2007; Ongür et al., 2008). In euthymia, studies have reported elevated Glx or Glu levels in the hippocampus, as well as in the orbitofrontal and occipital cortices (Bhagwagar et al., 2007; Colla et al., 2009; Senaratne et al., 2009), while a recent investigation from our group reported increased Glu and Glx levels in the ACC (Soeirode-Souza et al., 2013). "
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    ABSTRACT: The anterior cingulate cortex (ACC) is a key area in mood regulation. To date, no longitudinal study has specifically evaluated lithium׳s effects on ACC metabolites using (1)H-MRS, as well as its association with clinical improvement in bipolar depression. This (1)H-MRS (TE=35ms) study evaluated 24 drug-free BD patients during depressive episodes and after lithium treatment at therapeutic levels. Brain metabolite levels (N-acetyl aspartate (NAA), creatine (tCr), choline, myo-inositol, and glutamate levels) were measured in the ACC at baseline (week 0) and after lithium monotherapy (week 6). The present investigation showed that ACC glutamate (Glu/tCr) and glutamate+glutamine (Glx/tCr) significantly increased after six weeks of lithium therapy. Regarding the association with clinical improvement, remitters showed an increase in myoinositol levels (mI/tCr) after lithium treatment compared to non-remitters. The present findings reinforce a role for ACC glutamate-glutamine cycling and myoinositol pathway as key targets for lithium׳s therapeutic effects in BD.
    Full-text · Article · Sep 2015 · European neuropsychopharmacology: the journal of the European College of Neuropsychopharmacology
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    • "In bipolar disorder, the 1 H MRS studies are also mixed, with evidence of increased frontal (Castillo et al., 2000; Frye et al., 2007; Ongür et al., 2008), increased occipital (Bhagwagar et al., 2007) and decreased frontal (Port et al., 2008) GLU (or GLX) levels while there have also been reports of null findings in frontal (Davanzo et al., 2003; Moore et al., 2007), hippocampal (Gigante et al., 2014; Zanetti et al., 2014) and occipital (Davanzo et al., 2003) regions. A recent review (Yuksel and Ongur, 2010) has suggested that GLU may distinguish depressive from manic episodes, with reduced levels found to be consistent with the former and increased levels consistent with the latter. "
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    ABSTRACT: While numerous studies have employed magnetic resonance spectroscopy (MRS) to determine in vivo neurometabolite levels associated with mood disorders the findings in both unipolar depression and bipolar disorder have been mixed. Data-driven studies may shed new light on this literature by identifying distinct subgroups of patients who may benefit from different treatment strategies. The objective of the present study was to utilize hierarchical cluster analysis in order to generate new hypotheses with respect to neurometabolic profiling of mood disorder. Participants were 165 young persons (18-30 yrs) with a mood disorder and 40 healthy controls. Neurometabolite levels were recorded via proton-MRS ((1)H MRS). The ratios (relative to creatine) of glutamate (GLU), N-acetyl aspartate (NAA) and myo-inositol (MI) measured within the hippocampus. Self-reported and clinician rated symptoms as well as cognition were also measured. The unipolar depression (N=90) and bipolar disorder (N=75) groups did not significantly differ (from each other or controls) in their levels of GLU, NAA or MI. Cluster analyses derived four subgroups of patients who were distinguished by all three metabolites. There was a pattern of positive association between NAA and GLU, whereby clusters were abnormally increased (clusters 1, 2) or normal (cluster 4) or abnormally decreased (cluster 3) in these neurometabolites. These findings suggest that there are neurometabolic abnormalities in subgroups of young people with mood disorder, which may occur despite diagnostic similarities. Such evidence highlights that the underlying neurobiology of mood disorder is complex and MRS may have unique utility in delineating underlying neurobiology and targeting treatment strategies. Copyright © 2015 Elsevier B.V. and ECNP. All rights reserved.
    Full-text · Article · Feb 2015 · European Neuropsychopharmacology
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