The inhibitory neurotransmitter gamma-aminobutyric acid (GABA) has been implicated in the pathophysiology of depression. Therefore, we examined cerebrospinal fluid (CSF) levels of GABA in depressed patients (N = 25) and normal controls (N = 20). There was no significant difference between the groups. However, among the depressed patients the subgroup of unipolar melancholic patients (N = 13) had significantly lower CSF levels of GABA than the rest of the depressed patients (N = 12). There was no significant difference for CSF levels of GABA between depressed patients who were (N = 14) or were not (N = 11) cortisol non-suppressors. It was of interest that among the controls there was a significant negative correlation between CSF levels of GABA and CSF levels of norepinephrine.
"In the same study cohort, we previously reported reduced cortical GABA levels in TRD subjects compared to non-TRD and HC (Price et al., 2009). Other studies have found low cortical, CSF, and plasma GABA levels to be associated with anhedonic symptoms and melancholic depression (Gabbay et al., 2012; Petty et al., 1992; Roy et al., 1991; Sanacora et al., 2004). Levinson and colleagues have shown GABA-A receptor neurophysiological activity to be selectively impaired in TRD patients compared to non-TRD, euthymic MDD, and HC (Levinson et al., 2010). "
[Show abstract][Hide abstract] ABSTRACT: Hippocampal volume reduction has been related to treatment-resistant depression (TRD) and is hypothesized to reflect impaired amino-acid neurotransmission. To better understand the role of amino acid neurotransmission in hippocampal volume deficits, and subsequent resistance to treatment, this study investigated the relationship between hippocampal volumes and GABA levels in the anterior cingulate cortex (ACC), previously associated with TRD. Thirty-three medication-free major depressive disorder (MDD; 14 TRD and 19 non-TRD) and 26 healthy controls (HC) subjects were studied. Participants underwent high-resolution magnetic resonance imaging (MRI) to estimate hippocampal volume and proton MR spectroscopy ((1)H MRS) to measure ACC GABA levels. MDD patients, with known ACC GABA levels, were divided into two groups: MDD Low GABA and MDD High GABA. We found a significant reduction in hippocampal volume in the MDD Low GABA group compared to MDD High GABA (p<0.001) and HC (p=0.01). The relationship between hippocampal volume and cortical GABA was population (i.e. MDD group) and region specific (i.e. prefrontal cortex). Comparing TRD, non-TRD and HC groups, there was a main effect of group on hippocampal volume (p=0.04), which post hoc analysis revealed as smaller hippocampal volume in TRD subjects than in non-TRD (p=0.05) and HC groups (p=0.03). No hippocampal volume differences between non-TRD and HC groups. The data provides insight into the role of prefrontal neurochemical deficits in the limbic structural abnormalities observed in MDD. In addition, it replicates the relationship between TRD and smaller hippocampal volumes.
Published by Elsevier B.V.
European neuropsychopharmacology: the journal of the European College of Neuropsychopharmacology 05/2015; 25(8). DOI:10.1016/j.euroneuro.2015.04.025 · 4.37 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Stress response and depression have a significant impact on modern society. Although the symptoms are well characterized, the molecular mechanisms underlying depression are largely unknown. The monoamine hypothesis, which postulates dysfunctional noradrenergic and serotonergic systems as the underlying primary cause of depression, has been valuable for the development of conventional antidepressants, which can reverse these dysfunctional states to some degree. However, recent data from various neuroscience disciplines have questioned the major role of amines in the pathogenesis of depression. A considerable amount of evidence has accumulated that suggests that normalization of the hypothalamo-pituitary-adrenal (HPA) system might be the final step necessary for a remission of depression. In addition, an increasing body of clinical and postmortem evidence is pointing to a role played by γ-aminobutyric acid (GABA) and glutamate in the etiology of depression. This review examines the evidence, mainly obtained from clinical studies or from postmortem brain material, for a major role of the HPA axis, glutamatergic, and GABAergic systems in the pathogenesis of major and bipolar depression. The authors hope that these insights will stimulate further studies with the final aim of developing new types of antidepressants that combine increased efficacy with a shorter delay of the onset of action and reduced side-effect profiles.
The Neuroscientist 03/2010; 17(1):124-44. DOI:10.1177/1073858410361780 · 6.84 Impact Factor
"Therefore, our findings of positive correlations between KYN and 3-HAA and striatal tCho suggest that pathways involved in cellular survival may be more relevant to the pathogenesis of melancholic adolescent MDD compared to other subtypes of MDD. This notion is supported by findings from adult MDD studies documenting reductions of γaminobutyric acid (GABA) concentrations in the plasma (Petty et al., 1992), the CSF (Roy et al., 1991), and the occipital lobe (Sanacora et al., 2004) as well as increased glutamate brain concentrations (Sanacora et al., 2004), which were more pronounced in melancholic MDD patients compared to controls. "
[Show abstract][Hide abstract] ABSTRACT: Cytokine induction of the enzyme indoleamine 2,3-dioxygenase (IDO) has been implicated in the development of major depressive disorder (MDD). IDO metabolizes tryptophan (TRP) into kynurenine (KYN), thereby decreasing TRP availability to the brain. KYN is further metabolized into several neurotoxins. The aims of this pilot were to examine possible relationships between plasma TRP, KYN, and 3-hydroxyanthranilic acid (3-HAA, neurotoxic metabolite) and striatal total choline (tCho, cell membrane turnover biomarker) in adolescents with MDD. We hypothesized that MDD adolescents would exhibit: i) positive correlations between KYN and 3-HAA and striatal tCho and a negative correlation between TRP and striatal tCho; and, ii) the anticipated correlations would be more pronounced in the melancholic subtype group.
Fourteen adolescents with MDD (seven with melancholic features) and six healthy controls were enrolled. Minimums of 6 weeks MDD duration and a severity score of 40 on the Children's Depression Rating Scale-Revised were required. All were scanned at 3T with MRI, multi-voxel 3-dimensional, high, 0.75 cm(3), spatial resolution proton magnetic resonance spectroscopic imaging. Striatal tCho concentrations were assessed using phantom replacement. Spearman correlation coefficients were Bonferroni-corrected.
Positive correlations were found only in the melancholic group, between KYN and 3-HAA and tCho in the right caudate (r=0.93, p=0.03) and the left putamen (r=0.96, p=.006), respectively.
These preliminary findings suggest a possible role of the KYN pathway in adolescent melancholic MDD. Larger studies should follow.
Progress in Neuro-Psychopharmacology and Biological Psychiatry 09/2009; 34(1):37-44. DOI:10.1016/j.pnpbp.2009.09.015 · 3.69 Impact Factor
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