Contributions of Glutamate and GABA Systems to the Neurobiology and Treatment of Schizophrenia

Krystal, John H.; Moghaddam, Bita

doi:10.1002/9781444327298.ch21

Cited by 10 publications

(4 citation statements)

References 420 publications

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“…This approach did not explain cortical and PFC alterations associated with the progression of this illness (9). This work is now complemented by studies characterizing glutamate neurotransmission in schizophrenia (10)(11)(12)(13), pointing to alterations in the balance of excitation and inhibition in the cortical microcircuitry resulting from the hypofunction of the N-methyl-D-aspartate glutamate receptor (NMDAR) (14,15). This hypothesis is based on a key observation: subanesthetic doses of noncompetitive NMDAR antagonists such as ketamine produce cardinal symptoms resembling those of schizophrenia in healthy humans, including positive, negative, and cognitive aspects of the illness (16,17).…”

mentioning

confidence: 96%

N-Methyl-D-Aspartate Receptor Antagonist Effects on Prefrontal Cortical Connectivity Better Model Early Than Chronic Schizophrenia

Antičević

Corlett

Cole

et al. 2015

Biological Psychiatry

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mentioning

confidence: 96%

N-Methyl-D-Aspartate Receptor Antagonist Effects on Prefrontal Cortical Connectivity Better Model Early Than Chronic Schizophrenia

Antičević

Corlett

Cole

et al. 2015

Biological Psychiatry

Self Cite

153

135

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“…Almost every major neurotransmitter has been implicated, at one point or another, of playing a critical role in the etiology of schizophrenia, with greatest focus on the dopamine, glutamate and GABA systems. 27–29 More recent work has combined anatomical, molecular and neurochemical perspectives to develop more specific etiologicalanatomic theories (for example, Volk and Lewis 30 ).…”

Section: Schizophreniamentioning

confidence: 99%

The dappled nature of causes of psychiatric illness: replacing the organic–functional/hardware–software dichotomy with empirically based pluralism

2012

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Our tendency to see the world of psychiatric illness in dichotomous and opposing terms has three major sources: the philosophy of Descartes, the state of neuropathology in late nineteenth century Europe (when disorders were divided into those with and without demonstrable pathology and labeled, respectively, organic and functional), and the influential concept of computer functionalism wherein the computer is viewed as a model for the human mind–brain system (brain = hardware, mind = software). These mutually re-enforcing dichotomies, which have had a pernicious influence on our field, make a clear prediction about how ‘difference-makers’ (aka causal risk factors) for psychiatric disorders should be distributed in nature. In particular, are psychiatric disorders like our laptops, which when they dysfunction, can be cleanly divided into those with software versus hardware problems? I propose 11 categories of difference-makers for psychiatric illness from molecular genetics through culture and review their distribution in schizophrenia, major depression and alcohol dependence. In no case do these distributions resemble that predicted by the organic–functional/hardware–software dichotomy. Instead, the causes of psychiatric illness are dappled, distributed widely across multiple categories. We should abandon Cartesian and computer-functionalism-based dichotomies as scientifically inadequate and an impediment to our ability to integrate the diverse information about psychiatric illness our research has produced. Empirically based pluralism provides a rigorous but dappled view of the etiology of psychiatric illness. Critically, it is based not on how we wish the world to be but how the difference-makers for psychiatric illness are in fact distributed.

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“…Treatment with dopamine antagonists tends to alleviate these positive symptoms. Secondly, the brain's major excitatory neurotransmitter, glutamate, is implicated [2]. One proposal is that hypofunction of NMDA receptors (NMDAR) located on inhibitory GABA inter-neurons leads to reduced activity of these inter-neurons, resulting in increased pyramidal glutamatergic neurotransmission and the diverse symptoms occurring in acute psychosis [3].…”

Section: Introductionmentioning

confidence: 99%

Glutathione and glutamate in schizophrenia: a 7T MRS study

et al. 2018

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In schizophrenia, abnormal neural metabolite concentrations may arise from cortical damage following neuroinflammatory processes implicated in acute episodes. Inflammation is associated with increased glutamate, whereas the antioxidant glutathione may protect against inflammation-induced oxidative stress. We hypothesized that patients with stable schizophrenia would exhibit a reduction in glutathione, glutamate, and/or glutamine in the cerebral cortex, consistent with a post-inflammatory response, and that this reduction would be most marked in patients with "residual schizophrenia", in whom an early stage with positive psychotic symptoms has progressed to a late stage characterized by long-term negative symptoms and impairments. We recruited 28 patients with stable schizophrenia and 45 healthy participants matched for age, gender, and parental socio-economic status. We measured glutathione, glutamate and glutamine concentrations in the anterior cingulate cortex (ACC), left insula, and visual cortex using 7T proton magnetic resonance spectroscopy (MRS). Glutathione and glutamate were significantly correlated in all three voxels. Glutamine concentrations across the three voxels were significantly correlated with each other. Principal components analysis (PCA) produced three clear components: an ACC glutathione-glutamate component; an insula-visual glutathione-glutamate component; and a glutamine component. Patients with stable schizophrenia had significantly lower scores on the ACC glutathione-glutamate component, an effect almost entirely leveraged by the sub-group of patients with residual schizophrenia. All three metabolite concentration values in the ACC were significantly reduced in this group. These findings are consistent with the hypothesis that excitotoxicity during the acute phase of illness leads to reduced glutathione and glutamate in the residual phase of the illness.

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Contributions of Glutamate and GABA Systems to the Neurobiology and Treatment of Schizophrenia

Cited by 10 publications

References 420 publications

N-Methyl-D-Aspartate Receptor Antagonist Effects on Prefrontal Cortical Connectivity Better Model Early Than Chronic Schizophrenia

N-Methyl-D-Aspartate Receptor Antagonist Effects on Prefrontal Cortical Connectivity Better Model Early Than Chronic Schizophrenia

The dappled nature of causes of psychiatric illness: replacing the organic–functional/hardware–software dichotomy with empirically based pluralism

Glutathione and glutamate in schizophrenia: a 7T MRS study

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