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Behavioural and molecular endophenotypes in psychotic disorders reveal heritable abnormalities in glutamatergic neurotransmission.


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Authors

Scoriels, L 
Salek, RM 
Goodby, E 
Grainger, D 
Dean, AM 

Abstract

Psychotic disorders such as schizophrenia are biologically complex and carry huge population morbidity due to their prevalence, persistence and associated disability. Defined by features such as delusions and hallucinations, they involve cognitive dysfunction and neurotransmitter dysregulations that appear mostly to involve the dopaminergic and glutamatergic systems. A number of genetic and environmental factors are associated with these disorders but it has been difficult to identify the biological pathways underlying the principal symptoms. The endophenotype concept of stable, heritable traits that form a mechanistic link between genes and an overt expression of the disorder has potential to reduce the complexity of psychiatric phenotypes. In this study, we used a genetically sensitive design with individuals with a first episode of psychosis, their non-affected first-degree relatives and non-related healthy controls. Metabolomic analysis was combined with neurocognitive assessment to identify multilevel endophenotypic patterns: one concerned reaction times during the performance of cognitive and emotional tests that have previously been associated with the glutamate neurotransmission system, the other involved metabolites involved directly and indirectly in the co-activation of the N-methyl-D-aspartate receptor, a major receptor of the glutamate system. These cognitive and metabolic endophenotypes may comprise a single construct, such that genetically mediated dysfunction in the glutamate system may be responsible for delays in response to cognitive and emotional functions in psychotic disorders. This focus on glutamatergic neurotransmission should guide drug discovery and experimental medicine programmes in schizophrenia and related disorders.

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Keywords

Adult, Analysis of Variance, Chromatography, Liquid, Endophenotypes, Excitatory Amino Acids, Female, Genetic Predisposition to Disease, Glutamic Acid, Humans, Magnetic Resonance Spectroscopy, Male, Mass Spectrometry, Metabolomics, Neuropsychological Tests, Principal Component Analysis, Psychotic Disorders, Reaction Time, Receptors, N-Methyl-D-Aspartate, Synaptic Transmission, Young Adult

Journal Title

Transl Psychiatry

Conference Name

Journal ISSN

2158-3188
2158-3188

Volume Title

5

Publisher

Springer Science and Business Media LLC
Sponsorship
Medical Research Council (G0001354)
Medical Research Council (G0701911)
Medical Research Council (G1000183)
This study was funded by the Mason Medical Research Trust, the Stanley Medical Research Institute, the GlaxoSmithKlein and the Pinsent Darwin funding.