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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    • "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.
    European neuropsychopharmacology: the journal of the European College of Neuropsychopharmacology 09/2015; DOI:10.1016/j.euroneuro.2015.08.023 · 4.37 Impact Factor
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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.
    European Neuropsychopharmacology 02/2015; 25(6). DOI:10.1016/j.euroneuro.2015.02.009 · 4.37 Impact Factor
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    • "Both cellular energy production processes – through the coupling between glucose consumption and Glu-Gln cycling (Ende et al., 2000; Dager et al., 2008) – and GSK3 activity (Du et al., 2010) may influence glutamatergic transmission. While it has been hypothesized that depressive and manic episodes may be characterized by modulation of the Gln/ Glu ratio in opposite directions and also that BD would be associated with an overall increase in brain Glu or Glx levels (Yüksel and Öngür, 2010), the studies supporting this view have mostly enrolled patients under mood stabilizer medication and/ or with a chronic course (> 10 years) of illness (Frye et al., 2007; Colla et al., 2009; Gigante et al., 2012). Moreover, as low-dose lithium has been shown to be as effective as standard dose therapy – but associated with a A c c e p t e d M a n u s c r i p t 15 lower incidence of side effects – for the treatment of bipolar depression (Kleindienst et al., 2005; Machado-Vieira et al., 2009, 2014), the present finding raises the possibility that the use of lithium dosages with plasma levels higher than 0.50mmol/L increases the risk of regional toxic effects in the hippocampus due to overexposure to high Glu levels (Machado- Vieira et al., 2012). "
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    ABSTRACT: Hippocampus has been highly implicated in the pathophysiology of bipolar disorder (BD). Nevertheless, no study has longitudinally evaluated hippocampal metabolites levels in bipolar depression under treatment with lithium. Nineteen medication-free BD patients (78.9% treatment-naïve and 73.7% with BD type II) presenting an acute depressive episode and 17 healthy controls were studied. Patients were treated for 6 weeks with lithium in an open-label trial. N-acetyl aspartate (NAA), creatine, choline, myo-Inositol and glutamate levels were assessed in the left hippocampus before (week 0) and after lithium treatment (week 6) using 3T proton magnetic resonance spectroscopy (1H-MRS). The metabolite concentrations were estimated using internal water as reference and voxel segmentation for partial volume correction. At baseline, acutely depressed BD patients and healthy controls exhibited similar hippocampal metabolites concentrations, with no changes after 6 weeks of lithium monotherapy. A significant correlation between antidepressant efficacy and increases in NAA concentration over time was observed. Also, there was a significant positive correlation between the changes in glutamate concentrations over follow-up and plasma lithium levels at endpoint. Mixed effects model analysis revealed a bimodal effect of lithium plasma levels in hippocampal glutamate concentrations: levels of 0.2 to 0.49mmol/L (n=9) were associated with a decrease in glutamate concentrations, whereas the subgroup of BD subjects with "standard" lithium levels (= 0.50mmol/L) (n=10) showed an overall increase in glutamate concentrations over time. These preliminary results suggest that lithium has a bimodal action in hippocampal glutamate concentration depending on the plasma levels. Clinical trial number NCT01919892. © The Author 2014. Published by Oxford University Press on behalf of CINP.
    The International Journal of Neuropsychopharmacology 10/2014; 18(6). DOI:10.1093/ijnp/pyu058 · 4.01 Impact Factor
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