Frontal Glutamate and γ-Aminobutyric Acid Levels and Their Associations With Mismatch Negativity and Digit Sequencing Task Performance in Schizophrenia

Rowland, Laura M.; Summerfelt, Ann; Wijtenburg, S. Andrea; Du, Xiaoming; Chiappelli, Joshua; Krishna, Nithin; West, Jeffrey; Muellerklein, Florian; Kochunov, Peter; Hong, L. Elliot

doi:10.1001/jamapsychiatry.2015.2680

Cited by 83 publications

(69 citation statements)

References 67 publications

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“…[26][27][28][29][30] However, the quality of the spectral fits is not always clear in these reports (except for [27][28][29] ) and the samples were small (9 to 30 for the schizophrenia groups 6 ). More recent studies reported increases, [31][32][33][34][35] reductions 25,[36][37][38] and no differences 39 in Glx or glutamate. Two 33,34 of the 5 recent studies documenting elevations involved more ventral regions.…”

Section: Discussionmentioning

confidence: 99%

Glutamatergic and Neuronal Dysfunction in Gray and White Matter: A Spectroscopic Imaging Study in a Large Schizophrenia Sample

Bustillo

Jones

Chen

et al. 2016

SCHBUL

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Glutamine plus glutamate (Glx), as well as N-acetylaspartate compounds (NAAc, N-acetylaspartate plus N-acetyl-aspartyl-glutamate), a marker of neuronal viability, can be quantified with proton magnetic resonance spectroscopy ( 1 H-MRS). We used 1 H-MRS imaging to assess Glx and NAAc, as well as totalcholine (glycerophospho-choline plus phospho-choline), myo-inositol and total-creatine (creatine plus phosphocreatine) from an axial supraventricular slab of gray matter (GM, medial-frontal and medial-parietal) and white matter (WM, bilateral-frontal and bilateralparietal) voxels. Schizophrenia subjects (N = 104) and healthy controls (N = 97) with a broad age range (16 to 65) were studied. In schizophrenia, Glx was increased in GM (P < .001) and WM (P = .01), regardless of age. However, with greater age, NAAc increased in GM (P < .001) but decreased in WM (P < .001) in schizophrenia. In patients, total creatine decreased with age in WM (P < .001). Finally, overall cognitive score correlated positively with WM neurometabolites in controls but negatively in the schizophrenia group (NAAc, P < .001; and creatine [only younger], P < .001). We speculate the results support an ongoing process of increased glutamate metabolism in schizophrenia. Later in the illness, disease progression is suggested by increased cortical compaction without neuronal loss (elevated NAAc) and reduced axonal integrity (lower NAAc). Furthermore, this process is associated with fundamentally altered relationships between neurometabolite concentrations and cognitive function in schizophrenia.

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Section: Discussionmentioning

confidence: 99%

Glutamatergic and Neuronal Dysfunction in Gray and White Matter: A Spectroscopic Imaging Study in a Large Schizophrenia Sample

Bustillo

Jones

Chen

et al. 2016

SCHBUL

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“…There were 167 participants with MRS data and 105 participants with ASL data. Thirty-six of the 167 MRS datasets overlap with a previous study by Rowland et al (Rowland et al, 2016), and 30 of the 105 ASL datasets overlap with two previous studies by Wright et al (Wright et al, , 2015. Participant demographics are detailed in Table 1, and a breakdown of the antipsychotic medications being taking by adults with SZ are summarized in Supplementary Table 1.…”

Section: Participant Characteristicsmentioning

confidence: 98%

Altered Glutamate and Regional Cerebral Blood Flow Levels in Schizophrenia: A 1H-MRS and pCASL study

Wijtenburg

Wright

Korenic

et al. 2016

Neuropsychopharmacol

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The neurobiology of schizophrenia (SZ) may be altered in older versus younger adults with SZ, as less frequent episodes of symptom exacerbation and increased sensitivity to medications are observed in older age. The goal of this study was to examine the effect of age and diagnosis on glutamate and cerebral blood flow (rCBF) in adults with SZ and healthy controls. Young and older adults with SZ and healthy controls were recruited to participate in this study. Participants completed a neuropsychological battery and neuroimaging that included optimized magnetic resonance spectroscopy to measure anterior cingulate (AC) glutamate (Glu) and glutamine (Gln) and arterial spin labeling evaluation for rCBF. Regression analyses revealed significant effects of age with Glu, Gln, Gln/Glu, and AC white matter (WM) rCBF. Glu and WM rCBF decreased linearly with age while Gln and Gln/Glu increased linearly with age. Glu was lower in adults with SZ compared with healthy controls and in older adults versus younger adults but there was no interaction. Glu and WM rCBF were correlated with the UCSD Performance-Based Skills Assessment (UPSA) and processing speed, and the correlations were stronger in the SZ group. In the largest sample to date, lower Glu and elevated Gln/Glu levels were observed in adults with SZ and in older subjects. Contrary to expectation, these results do not show evidence of accelerated Glu aging in the anterior cingulate region in SZ compared with healthy controls.

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“…MMN functioning [130] occurs via interaction of NMDA [131] and α7nACh receptors [132-134]. In addition, smaller MMN amplitude was significantly associated with lower GABA and glutamate (measured by magnetic resonance spectroscopy) level in 45 people with schizophrenia compared to 53 healthy controls [135]. MMN deficits are tied to poor functional outcome [136, 137], as recently confirmed in a study of 1,415 subjects with schizophrenia.…”

Section: Mismatch Negativitymentioning

confidence: 99%

Potential Role of Antipsychotic-Galantamine-Memantine Combination in the Treatment of Positive, Cognitive, and Negative Symptoms of Schizophrenia

Koola¹

2018

Complex Psychiatry

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Schizophrenia is, in part, a cognitive illness. There are no approved medications for cognitive impairments associated with schizophrenia (CIAS) and primary negative symptoms. Cholinergic and glutamatergic systems, alpha-7 nicotinic acetylcholine (α-7nACh) and N-methyl-D-aspartate (NMDA) receptors, kynurenic acid (KYNA), and mismatch negativity have been implicated in the pathophysiology of CIAS and negative symptoms. Galantamine is an acetylcholinesterase inhibitor that is also a positive allosteric modulator at the α4β2 and α7nACh receptors. Memantine is a noncompetitive NMDA receptor antagonist. Galantamine and memantine alone and in combination were effective for cognition in animals and people with Alzheimer’s disease. The objective of this article is to critically dissect the published randomized controlled trials with galantamine and memantine for CIAS to highlight the efficacy signal. These studies may have failed to detect a clinically meaningful efficacy signal due to limitations, methodological issues, and possible medication nonadherence. There is evidence from a small open-label study that the galantamine-memantine combination may be effective for CIAS with kynurenine pathway metabolites as biomarkers to detect the severity of cognitive impairments. Given that there are no available treatments for cognitive impairments and primary negative symptoms in schizophrenia, testing of this “five-pronged strategy” (quintuple hypotheses: dopamine, nicotinic-cholinergic, glutamatergic/NMDA, GABA, and KYNA) is a “low-risk high-gain” approach that could be a major breakthrough in the field. The galantamine-memantine combination has the potential to treat positive, cognitive, and negative symptoms, and targeting the quintuple hypotheses concurrently may lead to a major scientific advancement – from antipsychotic treatment to antischizophrenia treatment.

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Frontal Glutamate and γ-Aminobutyric Acid Levels and Their Associations With Mismatch Negativity and Digit Sequencing Task Performance in Schizophrenia

Cited by 83 publications

References 67 publications

Glutamatergic and Neuronal Dysfunction in Gray and White Matter: A Spectroscopic Imaging Study in a Large Schizophrenia Sample

Glutamatergic and Neuronal Dysfunction in Gray and White Matter: A Spectroscopic Imaging Study in a Large Schizophrenia Sample

Altered Glutamate and Regional Cerebral Blood Flow Levels in Schizophrenia: A 1H-MRS and pCASL study

Potential Role of Antipsychotic-Galantamine-Memantine Combination in the Treatment of Positive, Cognitive, and Negative Symptoms of Schizophrenia

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