Targeting glutamate to treat schizophrenia: lessons from recent clinical studies

Beck, Katherine; Javitt, Daniel C.; Howes, Oliver

doi:10.1007/s00213-016-4318-6

Cited by 24 publications

(19 citation statements)

References 26 publications

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“…As discussed in detail above, KAT inhibition is actively pursued as a strategy for treatment of schizophrenia. [116][117][118][119][120] Kynureninase inhibition can also be a strategy to lower QA levels in neurodegenerative conditions, such as the Huntingdon and Alzheimer diseases and AIDS dementia. Various compounds with moderately potent inhibitory potencies have been developed.…”

Section: Disturbances In Kp Enzymes In Disease and Their Inhibition Imentioning

confidence: 99%

Kynurenine Pathway of Tryptophan Metabolism: Regulatory and Functional Aspects

Badawy

2017

Int J�Tryptophan�Res

783

831

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Regulatory and functional aspects of the kynurenine (K) pathway (KP) of tryptophan (Trp) degradation are reviewed. The KP accounts for ~95% of dietary Trp degradation, of which 90% is attributed to the hepatic KP. During immune activation, the minor extrahepatic KP plays a more active role. The KP is rate-limited by its first enzyme, Trp 2,3-dioxygenase (TDO), in liver and indoleamine 2,3-dioxygenase (IDO) elsewhere. TDO is regulated by glucocorticoid induction, substrate activation and stabilization by Trp, cofactor activation by heme, and end-product inhibition by reduced nicotinamide adenine dinucleotide (phosphate). IDO is regulated by IFN-γ and other cytokines and by nitric oxide. The KP disposes of excess Trp, controls hepatic heme synthesis and Trp availability for cerebral serotonin synthesis, and produces immunoregulatory and neuroactive metabolites, the B3 “vitamin” nicotinic acid, and oxidized nicotinamide adenine dinucleotide. Various KP enzymes are undermined in disease and are targeted for therapy of conditions ranging from immunological, neurological, and neurodegenerative conditions to cancer.

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Section: Disturbances In Kp Enzymes In Disease and Their Inhibition Imentioning

confidence: 99%

Kynurenine Pathway of Tryptophan Metabolism: Regulatory and Functional Aspects

Badawy

2017

Int J�Tryptophan�Res

783

831

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“…Bitopertin, a glycine type I transporter inhibitor, appeared to be a promising compound in this regard, showing good blood‐brain barrier penetration, with encouraging results in early clinical trials. However, later trials were not successful, perhaps due to the unusually high placebo responses, or the use of chronic patient populations, given that there is some evidence that intervention is likely to be more effective in early illness stages.…”

Section: Treatmentmentioning

confidence: 99%

Dopamine and glutamate in schizophrenia: biology, symptoms and treatment

2020

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Glutamate and dopamine systems play distinct roles in terms of neuronal signalling, yet both have been proposed to contribute significantly to the pathophysiology of schizophrenia. In this paper we assess research that has implicated both systems in the aetiology of this disorder. We examine evidence from post‐mortem, preclinical, pharmacological and in vivo neuroimaging studies. Pharmacological and preclinical studies implicate both systems, and in vivo imaging of the dopamine system has consistently identified elevated striatal dopamine synthesis and release capacity in schizophrenia. Imaging of the glutamate system and other aspects of research on the dopamine system have produced less consistent findings, potentially due to methodological limitations and the heterogeneity of the disorder. Converging evidence indicates that genetic and environmental risk factors for schizophrenia underlie disruption of glutamatergic and dopaminergic function. However, while genetic influences may directly underlie glutamatergic dysfunction, few genetic risk variants directly implicate the dopamine system, indicating that aberrant dopamine signalling is likely to be predominantly due to other factors. We discuss the neural circuits through which the two systems interact, and how their disruption may cause psychotic symptoms. We also discuss mechanisms through which existing treatments operate, and how recent research has highlighted opportunities for the development of novel pharmacological therapies. Finally, we consider outstanding questions for the field, including what remains unknown regarding the nature of glutamate and dopamine function in schizophrenia, and what needs to be achieved to make progress in developing new treatments.

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“…The observation that glutamate is linked to and affects personality could be used as a treatment option to reduce symptoms of psychotic and other psychiatric disorders ( Carlsson, 2001 ; Rosenberg et al, 2004 ; Hoerst et al, 2010 ; Neill and Frodl, 2012 ). However, since SCZ is a very heterogeneous disorder, it is possible that different types of treatment will be necessary to help to diminish the diverse symptoms in this patient group ( Chavez-Noriega et al, 2002 ; Howes and Kapur, 2014 ; Poels et al, 2014b ; Beck et al, 2016 ). Promising results supporting this therapeutic avenue propose that SCZ who do not respond to dopaminergic medication reveal normal dopaminergic levels, but altered glutamate levels ( Demjaha et al, 2014 ).…”

Section: Discussionmentioning

confidence: 99%

Glutamate Concentration in the Superior Temporal Sulcus Relates to Neuroticism in Schizophrenia

et al. 2018

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Clinical studies suggest aberrant neurotransmitter concentrations in the brains of patients with schizophrenia (SCZ). Numerous studies have indicated deviant glutamate concentrations in SCZ, although the findings are inconsistent. Moreover, alterations in glutamate concentrations could be linked to personality traits in SCZ. Here, we examined the relationships between personality dimensions and glutamate concentrations in a voxel encompassing the occipital cortex (OCC) and another voxel encompassing the left superior temporal sulcus (STS). We used proton magnetic resonance spectroscopy to examine glutamate concentrations in the OCC and the STS in 19 SCZ and 21 non-psychiatric healthy control (HC) participants. Personality dimensions neuroticism, extraversion, openness, agreeableness and conscientiousness were assessed using the NEO-FFI questionnaire. SCZ compared to HC showed higher glutamate concentrations in the STS, reduced extraversion scores, and enhanced neuroticism scores. No group differences were observed for the other personality traits and for glutamate concentrations in the OCC. For the SCZ group, glutamate concentrations in STS were negatively correlated with the neuroticism scores [r = -0.537, p = 0.018] but this was not found in HC [r(19) = 0.011, p = 0.962]. No other significant correlations were found. Our study showed an inverse relationship between glutamate concentrations in the STS and neuroticism scores in SCZ. Elevated glutamate in the STS might serve as a compensatory mechanism that enables patients with enhanced concentrations to control and prevent the expression of neuroticism.

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Targeting glutamate to treat schizophrenia: lessons from recent clinical studies

Cited by 24 publications

References 26 publications

Kynurenine Pathway of Tryptophan Metabolism: Regulatory and Functional Aspects

Kynurenine Pathway of Tryptophan Metabolism: Regulatory and Functional Aspects

Dopamine and glutamate in schizophrenia: biology, symptoms and treatment

Glutamate Concentration in the Superior Temporal Sulcus Relates to Neuroticism in Schizophrenia

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