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

ArticleinArchives of General Psychiatry 56(11):1043-7 · December 1999with7 Reads
DOI: 10.1001/archpsyc.56.11.1043 · Source: PubMed
Abstract
Several lines of emerging evidence suggest that dysfunction of gamma-aminobutyric acid (GABA) systems is associated with major depression. However, investigation of this hypothesis is limited by difficulty obtaining noninvasive in vivo measures of brain GABA levels. In this study we used in vivo proton magnetic resonance spectroscopy to investigate the hypothesis that abnormalities in the GABA neurotransmitter system are associated with the neurobiologic processes of depression. The GABA levels were measured in the occipital cortex of medication-free depressed patients meeting DSM-IV criteria (n = 14) and healthy control subjects with no history of mental illness (n = 18) using a localized difference editing proton magnetic resonance spectroscopy protocol. An analysis of covariance was employed to examine the effects of depression, sex, and age. The depressed patients demonstrated a highly significant (52%) reduction in occipital cortex GABA levels compared with the group of healthy subjects. While there were significant age and sex effects, there was no interaction of diagnosis with either age or sex. This study provides the first evidence of abnormally low cortical GABA concentrations in the brains of depressed patients.
    • "Thus, an elevation of glutamate may stimulate GABAergic neurons to release GABA. Since 1999, when Gerard Sanacora showed that -aminobutyric acid levels are reduced in depressed patients [45], increasing evidence has indicated that MDD is associated with altered functions of the major excitatory and inhibitory neurotransmitters , glutamate and GABA, respectively [46,47]. The elevated hippocampal GABA levels we observed here in the DG-and VLXtreated mice suggested that DG might exert an antidepressant effect by upregulating GABA. "
    [Show abstract] [Hide abstract] ABSTRACT: Ginkgo biloba extract (GBE), including EGb-761, have been suggested to have antidepressant activity based on previous behavioral and biochemical analyses. However, because GBE contain many constituents, the mechanisms underlying this suggested antidepressant activity are unclear. Here, we investigated the antidepressant-like effects of diterpene ginkgolides (DG), an important class of constituents in GBE, and studied their effects in the mouse hippocampus using a GC-MS-based metabolomics approach. Mice were randomly divided into five groups and injected daily until testing with 0.9% NaCl solution, one of three doses of DG (4.06, 12.18, and 36.54mg/kg), or venlafaxine. Sucrose preference (SPT) and tail suspension (TST) tests were then performed to evaluate depressive-like behaviors in mice. DG (12.18 and 36.54mg/kg) and venlafaxine (VLX) administration significantly increased hedonic behavior in mice in the SPT. DG (12.18mg/kg) treatment also shortened immobility time in the TST, suggestive of antidepressant-like effects. Significant differences in the metabolic profile in the DG (12.18mg/kg) compared with the control or VLX group indicative of an antidepressant-like effect were observed using multivariate analysis. Eighteen differential hippocampal metabolites were identified that discriminated the DG (12.18mg/kg) and control groups. These biochemical changes involved neurotransmitter metabolism, oxidative stress, glutathione metabolism, lipid metabolism, energy metabolism, and kynurenic acid, providing clues to the therapeutic mechanisms of DG. Thus, this study showed that DG has antidepressant-like activities in mice and shed light on the biological mechanisms underlying the effects of diterpene ginkgolides on behavior, providing an important drug candidate for the treatment of depression.
    Full-text · Article · Aug 2016
    • "Significant heterogeneity was found for studies on MDD (P < 0.001, I 2 5 68%), on current MDD (P < 0.001, I 2 5 74%), but not on remitted MDD (P 5 0.07, I 2 5 49%). Exclusion of the study with the largest SMD [Sanacora et al., 1999] reduced heterogeneity but it remained significant (P 5 0.003; I 2 5 55%). A comparably large heterogeneity was found for schizophrenia studies (P < 0.001, I 2 5 67%). "
    [Show abstract] [Hide abstract] ABSTRACT: The inhibitory gamma-aminobutyric acid (GABA) system is involved in the etiology of most psychiatric disorders, including schizophrenia, autism spectrum disorder (ASD) and major depressive disorder (MDD). It is therefore not surprising that proton magnetic resonance spectroscopy ((1) H-MRS) is increasingly used to investigate in vivo brain GABA levels. However, integration of the evidence for altered in vivo GABA levels across psychiatric disorders is lacking. We therefore systematically searched the clinical (1) H-MRS literature and performed a meta-analysis. A total of 40 studies (N = 1,591) in seven different psychiatric disorders were included in the meta-analysis: MDD (N = 437), schizophrenia (N = 517), ASD (N = 150), bipolar disorder (N = 129), panic disorder (N = 81), posttraumatic stress disorder (PTSD) (N = 104), and attention deficit/hyperactivity disorder (ADHD) (N = 173). Brain GABA levels were lower in ASD (standardized mean difference [SMD] = -0.74, P = 0.001) and in depressed MDD patients (SMD = -0.52, P = 0.005), but not in remitted MDD patients (SMD = -0.24, P = 0.310) compared with controls. In schizophrenia this finding did not reach statistical significance (SMD = -0.23, P = 0.089). No significant differences in GABA levels were found in bipolar disorder, panic disorder, PTSD, and ADHD compared with controls. In conclusion, this meta-analysis provided evidence for lower brain GABA levels in ASD and in depressed (but not remitted) MDD patients compared with healthy controls. Findings in schizophrenia were more equivocal. Even though future (1) H-MRS studies could greatly benefit from a longitudinal design and consensus on the preferred analytical approach, it is apparent that (1) H-MRS studies have great potential in advancing our understanding of the role of the GABA system in the pathogenesis of psychiatric disorders. Hum Brain Mapp, 2016. © 2016 Wiley Periodicals, Inc.
    Article · May 2016
    • "In our study depression comorbidity was present in all subjects, raising the question whether low GABAp would be a biomarker of depression or a core symptom of PTSD? Depression is associated with decreased GABA concentrations at cerebral (Bhagwagar et al., 2004; Sanacora et al., 1999 Sanacora et al., , 2002 Sanacora et al., , 2003) and plasma (Petty, 1981Petty, , 1995 Petty and Sherman, 1984; Petty et al., 1997 Petty et al., , , 1993) levels. The same is reported in non depressive PTSD patients (Rossi et al., 2009). "
    [Show abstract] [Hide abstract] ABSTRACT: Objectives: An increased reactivity to the environment is observed in Post-Traumatic Stress Disorder (PTSD). It would be related to impairment of the Gamma Amino Butyric Acid (GABA) neurotransmission. The study aimed to evaluate plasma GABA concentration as a candidate for PTSD severity biomarker. Methods: This hypothesis was studied in 17 PTSD patients and 17 healthy Controls using classic and emotional Stroop paradigms. Plasma GABA concentrations were assessed before and after both Stroop tests to evaluate GABA basal tone and GABA reactivity (change in GABAp), respectively. Results: During baseline, PTSD had lower plasma GABA concentrations than the Controls. After the Stroop conflicts GABA reactivity was also lower in PTSD than in the Controls. The GABA baseline tone was negatively correlated with the severity of the PTSD symptoms. This relation was only marginally observed for GABA reactivity. The results produced a trend due to the small size of the sample compared to the number of statistical results given. Conclusion: Altogether, the reduced GABA concentration observed in PTSD could be considered as a possible biomarker for PTSD severity.
    Full-text · Article · May 2016
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