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

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.

Differing patterns of brain structural abnormalities between black and white patients with their first episode of psychosis

BACKGROUND: African-Caribbean and black African people living in the UK are reported to have a higher incidence of diagnosed psychosis compared with white British people. It has been argued that this may be a consequence of misdiagnosis. If this is true they might be less likely to show the patterns of structural brain abnormalities reported in white British patients. The aim of this study therefore was to investigate whether there are differences in the prevalence of structural brain abnormalities in white and black first-episode psychosis patients. METHOD: We obtained dual-echo (proton density/T2-weighted) images from a sample of 75 first-episode psychosis patients and 68 healthy controls. We used high resolution magnetic resonance imaging and voxel-based methods of image analysis. Two separate analyses were conducted: (1) 34 white British patients were compared with 33 white British controls; (2) 41 African-Caribbean and black African patients were compared with 35 African-Caribbean and black African controls. RESULTS: White British patients and African-Caribbean/black African patients had ventricular enlargement and increased lenticular nucleus volume compared with their respective ethnic controls. The African-Caribbean/black African patients also showed reduced global grey matter and increased lingual gyrus grey-matter volume. The white British patients had no regional or global grey-matter loss compared with their normal ethnic counterparts but showed increased grey matter in the left superior temporal lobe and right parahippocampal gyrus. CONCLUSIONS: We found no evidence in support of our hypothesis. Indeed, the finding of reduced global grey-matter volume in the African-Caribbean/black African patients but not in the white British patients was contrary to our prediction.

Psychoses, ethnicity and socio-economic status.

BACKGROUND: Consistent observation of raised rates of psychoses among Black and minority ethnic (BME) groups may possibly be explained by their lower socio-economic status. AIMS: To test whether risk for psychoses remained elevated in BME populations compared with the White British, after adjustment for age, gender and current socio-economic status. METHOD: Population-based study of first-episode DSM-IV psychotic disorders, in individuals aged 18-64 years, in East London over 2 years. RESULTS: All BME groups had elevated rates of a psychotic disorder after adjustment for age, gender and socio-economic status. For schizophrenia, risk was elevated for people of Black Caribbean (incidence rate ratios (IRR)=3.1, 95% CI 2.1-4.5) and Black African (IRR=2.6, 95% CI 1.8-3.8) origin, and for Pakistani (IRR=3.1, 95% CI 1.2-8.1) and Bangladeshi (IRR=2.3, 95% CI 1.1-4.7) women. Mixed White and Black Caribbean (IRR=7.7, 95% CI 3.2-18.8) and White Other (IRR=2.1, 95% CI 1.2-3.8) groups had elevated rates of affective psychoses (and other non-affective psychoses). CONCLUSIONS: Elevated rates of psychoses in BME groups could not be explained by socio-economic status, even though current socio-economic status may have overestimated the effect of this confounder given potential misclassification as a result of downward social drift in the prodromal phase of psychosis. Our findings extended to all BME groups and psychotic disorders, though heterogeneity remains.

Grey matter correlates of minor physical anomalies in the AESOP first-episode psychosis study

BACKGROUND: Minor physical anomaliesare more prevalent among people withpsychosis. This supports aneurodevelopmental aetiology forpsychotic disorders, since these anomalies and the brain are both ectodermally derived. However, little is understood about the brain regions implicated in this association. AIMS: To examine the relationship between minor physical anomalies and grey matter structure in a sample of patients with first-episode psychosis. METHOD: Sixty patients underwent assessment of minor physical anomalies with the Lane scale. High-resolution magnetic resonance images and voxel-based methods of image analysis were used to investigate brain structure in these patients. RESULTS: The total anomalies score was associated with a grey matter reduction in the prefrontal cortex and precuneus and with a grey matter excess in the basal ganglia, thalamus and lingual gyrus. CONCLUSIONS: Minor physical anomalies in a sample of patients with first-episode psychosis are associated with regionalgrey matter changes. These regional changes may be important in the pathogenesis of psychotic disorder.