Subtype-Specific Alterations of γ-Aminobutyric Acid and Glutamatein Patients With Major Depression

Sanacora, Gerard; Gueorguieva, Ralitza; Epperson, C. Neill; Wu, Yu‐Te; Appel, Michael C.; Rothman, Douglas L.; Krystal, John H.; Mason, Graeme F.

doi:10.1001/archpsyc.61.7.705

Cited by 733 publications

(535 citation statements)

References 70 publications

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“…Our preliminary results are in contrast to the Sanacora et al (2004) study which found below-normal glutamate and abovenormal GABA in the occipital lobes in melancholic unipolar patients. It is important to emphasize however, that the two studies differ in primary cohort (bipolar vs unipolar) and brain region of interest (anterior cingulated/medial prefrontal cortex vs occipital lobe).…”

Section: Discussioncontrasting

confidence: 99%

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

Frye

Watzl

Banakar

et al. 2007

Neuropsychopharmacol

202

127

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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 ¼ 30/3000 ms, 3 Â 3 Â 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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Section: Discussioncontrasting

confidence: 99%

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

Frye

Watzl

Banakar

et al. 2007

Neuropsychopharmacol

202

127

View full text Add to dashboard Cite

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“…The observations presented here, suggesting a deficit in GABAergic neurons in depression, are supported by recent clinical reports of reduced GABA levels in plasma and cerebrospinal fluid in mood disorder patients (Brambilla et al, 2003;Petty, 1995;Sanacora et al, 1999Sanacora et al, , 2004. A proton magnetic resonance spectroscopy study in live patients shows a highly significant 52% reduction in GABA levels in the occipital cortex of 14 medication-free depressed subjects (Sanacora et al, 1999).…”

Section: Discussionsupporting

confidence: 87%

“…No significant differences in the density of calbindin-immunoreactive (CB-IR) or parvalbumin-immunoreactive (PV-IR) GABAergic neurons were found between MDD and control groups in either cortical region. However, clinical evidence is emerging to suggest that MDD is associated with reduced levels of GABA in the plasma, cerebrospinal fluid, and neocortex (Petty, 1995;Sanacora et al, 1999Sanacora et al, , 2000Sanacora et al, , 2004. A proton magnetic resonance spectroscopy study revealed a large, 52% reduction in GABA levels in the occipital cortex of 14 medication-free depressed subjects as compared to 18 healthy control subjects (Sanacora et al, 1999).…”

Section: Introductionmentioning

confidence: 99%

GABAergic Neurons Immunoreactive for Calcium Binding Proteins are Reduced in the Prefrontal Cortex in Major Depression

Rajkowska

O'Dwyer

Teleki

et al. 2006

Neuropsychopharmacol

373

234

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Post-mortem morphometric studies report reductions in the average density and size of cortical neurons in the dorsolateral prefrontal cortex (dlPFC) and orbitofrontal cortex (ORB) in major depressive disorder (MDD). The contribution of specific neuronal phenotypes to this general pathology in depression is still unclear. Post-mortem sections from the dlPFC and ORB regions of 14 subjects with MDD and 11 controls were immunostained to visualize calbindin-immunoreactive (CB-IR) and parvalbumin-immunoreactive (PV-IR) presumptive GABAergic neurons. A three-dimensional cell counting probe was used to assess the cell packing density and size of CB-IR neurons in layers II + IIIa and PV-IR neurons in layers III-VI. The density of CB-IR neurons was significantly reduced by 50% in depression in the dlPFC and there was a trend toward reduction in the ORB. The size of CB-IR somata was significantly decreased (18%) in depression in the dlPFC with a trend toward reduction in the ORB. In contrast, there was no difference in the density of PV-IR neurons between the depressed and control groups in the dlPFC. The size of PV-IR neuronal soma was unchanged in depressed compared to control subjects in either dlPFC or ORB. In depression, subpopulations of GABAergic neurons may be affected differently in dlPFC and ORB. A significant reduction in the density and size of GABAergic interneurons immunoreactive for calcium binding proteins was found predominantly in the dlPFC region. These cellular changes are consistent with recent neuroimaging studies revealing a reduction in the cortical levels of GABA in depression.

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“…[43][44][45][46] The observation of a significant misexpression of molecules central to both GABAergic and glutamatergic neurotransmission in the cortical areas of individuals with major depression has been previously documented by several groups. 21,23,47 These studies follow on a body of clinical evidence showing that antidepressant medications may reduce glutamatergic activity while raising cortical GABA levels, which are seen to be reduced in major depression 48,49 and possibly also schizophrenia. 50,51 Since the two neurotransmitters are intimately connected by virtue of interconversion through glutamic acid decarboxylase in the synthesis of GABA from glutamate and the TCA cycle in the production of glutamate from GABA, it is difficult to disentangle the possible effects of these two molecules on the pathophysiology of depression and suicide.…”

Section: Discussionmentioning

confidence: 99%

“…In general, a growing body of evidence supports the involvement of GABA/ glutamate in cortical regions typified by BA46 in the DLPFC. [21][22][23] Two genes involved in the catabolism of polyamines (SAT and SMOX), significant in several regions, suggest the possible association of suicide and depression with defects in the polyamine stress response system. Reduced expression of SAT in depressed and nondepressed suicide groups was previously shown in motor cortex, superior frontal gyrus and orbital gyrus, 9 with correspondingly reduced levels of SAT protein.…”

Section: Discussionmentioning

confidence: 99%

Altered expression of genes involved in ATP biosynthesis and GABAergic neurotransmission in the ventral prefrontal cortex of suicides with and without major depression

et al. 2007

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The prefrontal cortex is believed to play a major role in depression and suicidal behavior through regulation of cognition, memory, recognition of emotion, and anxiety-like states, with numerous post-mortem studies documenting a prefrontal serotonergic dysregulation considered to be characteristic of depressive psychopathology. This study was carried out to detect changes in gene expression associated with both suicide and major depression using oligonucleotide microarrays (Affymetrix HG-U133 chip set) summarizing expression patterns in primarily ventral regions of the prefrontal cortex (BA44, 45, 46 and 47). A total of 37 male subjects were included in this study, of which 24 were suicides (depressed suicides = 16, nondepressed suicides = 8) and 13 were matched controls. All subjects were clinically characterized by means of psychological autopsies using structured interviews. Unique patterns of differential expression were validated in each of the cortical regions evaluated, with group-specific changes highlighting the involvement of several key neurobiological pathways that have been implicated in both suicide and depression. An overrepresentation of factors involved in cell cycle control and cell division (BA44), transcription (BA44 and 47) and myelination (BA46) was seen in gene ontology analysis of differentially expressed genes, which also highlights changes in the expression of genes involved in ATP biosynthesis and utilization across all areas. Gene misexpression in BA46 was most pronounced between the two suicide groups, with many significant genes involved in GABAergic neurotransmission. The pronounced misexpression of genes central to GABAergic signaling and astrocyte/ oligodendrocyte function provides further support for a central glial pathology in depression and suicidal behavior.

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Subtype-Specific Alterations of γ-Aminobutyric Acid and Glutamatein Patients With Major Depression

Cited by 733 publications

References 70 publications

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

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

GABAergic Neurons Immunoreactive for Calcium Binding Proteins are Reduced in the Prefrontal Cortex in Major Depression

Altered expression of genes involved in ATP biosynthesis and GABAergic neurotransmission in the ventral prefrontal cortex of suicides with and without major depression

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