Reduced Cortical γ-Aminobutyric Acid Levels in Depressed Patients Determined by Proton Magnetic Resonance Spectroscopy

Sanacora, Gerard; Mason, Graeme F.; Rothman, Douglas L.; Behar, Kevin L.; Hyder, Fahmeed; Petroff, Ognen A. C.; Berman, R.; Charney, Dennis S.; Krystal, John H.

doi:10.1001/archpsyc.56.11.1043

Cited by 552 publications

(421 citation statements)

References 33 publications

(39 reference statements)

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“…Also, SSRIs are known to increase GABA levels in the brain of depressed patients. 98 Finally, our results also confirm the recent findings of another group concerning gene expression abnormalities in GABA signal transmission in the cerebral cortex of subjects, who had suffered from depression and more specifically GABA(A) and GABA(B) alterations in individuals who died by suicide suggesting their potential role in suicidality. 62 Our findings together with previous studies clearly point to an alteration of gabaergic neurotransmission in suicide and major depression in the context of suicide and offers new potential pharmacological targets for the treatment of such complex disorders.…”

Section: Discussionsupporting

confidence: 91%

Patterns of gene expression in the limbic system of suicides with and without major depression

et al. 2007

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The limbic system has consistently been associated with the control of emotions and with mood disorders. The goal of this study was to identify new molecular targets associated with suicide and with major depression using oligonucleotide microarrays in the limbic system (amygdala, hippocampus, anterior cingulate gryus (BA24) and posterior cingulate gyrus (BA29)). A total of 39 subjects were included in this study. They were all male subjects and comprised 26 suicides (depressed suicides = 18, non depressed suicides = 8) and 13 matched controls. Brain gene expression analysis was carried out on human brain samples using the Affymetrix HG U133 chip set. Differential expression in each of the limbic regions showed group-specific patterns of expression, supporting particular neurobiological mechanisms implicated in suicide and depression. Confirmation of genes selected based on their significance and the interest of their function with reverse transcriptase-polymerase chain reaction showed consistently correlated signals with the results obtained in the microarray analysis. Gene ontology analysis with differentially expressed genes revealed an overrepresentation of transcription and metabolism-related genes in the hippocampus and amygdala, whereas differentially expressed genes in BA24 and BA29 were more generally related to RNA-binding, regulation of enzymatic activity and protein metabolism. Limbic expression patterns were most extensively altered in the hippocampus, where processes related to major depression were associated with altered expression of factors involved with transcription and cellular metabolism. Additionally, our results confirm previous evidence pointing to global alteration of gabaergic neurotransmission in suicide and major depression, offering new avenues in the study and possibly treatment of such complex disorders. Overall, these data suggest that specific patterns of expression in the limbic system contribute to the etiology of depression and suicidal behaviors and highlight the role of the hippocampus in major depression.

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Section: Discussionsupporting

confidence: 91%

Patterns of gene expression in the limbic system of suicides with and without major depression

et al. 2007

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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%

“…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). Later studies by the same investigators demonstrated that low levels of GABA in the occipital cortex in depressed patients can be reversed by treatment with selective serotonin reuptake inhibitors (SSRIs) or ECT (Sanacora et al, 2002(Sanacora et al, , 2003a.…”

Section: Introductionmentioning

confidence: 99%

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

Rajkowska

O'Dwyer

Teleki

et al. 2006

Neuropsychopharmacol

352

225

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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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“…Higher field strength may better quantify Gln and separate it from Glu as evidenced by a 4-T study of left anterior cingulate finding reductions in both Glu and Gln in schizophrenia (Theberge et al, 2003). Furthermore, in addition to the Glu and Gln included in the LCModel fit of the Glx signal, some authors include a GABA contribution since their curve fitting algorithms do not differentiate GABA from the overlapping Glx peaks (Sanacora et al, 1999); nonetheless, this contribution is considered to be quite small.…”

Section: Discussionmentioning

confidence: 99%

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

Frye

Watzl

Banakar

et al. 2007

Neuropsychopharmacol

198

126

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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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Reduced Cortical γ-Aminobutyric Acid Levels in Depressed Patients Determined by Proton Magnetic Resonance Spectroscopy

Abstract: This study provides the first evidence of abnormally low cortical GABA concentrations in the brains of depressed patients.

Cited by 552 publications

References 33 publications

Patterns of gene expression in the limbic system of suicides with and without major depression

Patterns of gene expression in the limbic system of suicides with and without major depression

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

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

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