Schizophrenia and identifying those at high risk – the LJ Seidman memorial lecture

Two presentations featured different aspects of the earlier identification of those at high risk of schizophrenia.

Consortium on the Genetics of Schizophrenia (COGS)

Professor David Braff, San Diego, California, USA, presented data from the Consortium on the Genetics of Schizophrenia (COGS). COGS is a multi-center, family-based effort to apply a comprehensive endophenotypic approach to schizophrenia. Endophenotypes are quantitative, heritable, trait-related deficits typically assessed either by laboratory-based methods rather than by clinical observation.

COGS uses schizophrenia-associated endophenotypes to identify linkage regions associated with specific heritable neurocognitive and neurophysiological deficits that can be assessed reliable between research sites. Complementary to this approach is the creation of the COGS customized 1536 single nucleotide polymorphism (SNP) chip for schizophrenia. This gene chip contains 1536 SNPs in 94 genes that have been determined to be of relevance in schizophrenia. The chip can be used to check whether any of the candidate genes and the endophenotypes characteristics are associated.

To date, promising signals have arisen. Many of the genes interact on a molecular level, and some appear pleiotropic e.g. NRG1 and ERBB4, revealing associations with multiple endophenotypes.

Overall, Professor Braff reported, the results to date collectively support a strong role for genes related to glutamate signaling in potentially mediating schizophrenia susceptibility.

Therapies targeting glutamate signaling may be of value in identifying those at high risk of schizophrenia

North American Prodrome Longitudinal Study (NAPLS)

Tyrone Cannon, Yale, Connecticut, USA, described the North American Prodrome Longitudinal Study (NAPLS) which sought clues as how best to predict conversion in those at high risk of psychosis.

Clinical, demographic and cognitive data that were likely to predict conversion to psychosis and that could be easily assayed in the clinical setting were gathered from individuals experiencing prodromal symptoms. These were used to create a risk calculator – a web-based tool that estimates the risk of conversion to psychosis in new cases.

Factors considered the most useful in generating the risk score were increased severity of unusual thoughts, increased suspiciousness, slow processing speed, poor verbal list learning performance and decline in social functioning 1 year prior to assessment. Use of the risk calculator could help facilitate a stepped-care approach, where less invasive intervention could be used in those at lower risk of psychosis. 

Use of the risk calculator could help facilitate a stepped care approach, with less invasive interventions being given to those at lower risk

A NAPLS longitudinal MRI study also has shown that those who convert to psychosis experience a steeper rate of grey matter loss in the pre-frontal cortex than non-converters. Furthermore, it appears that proinflammatory cytokine levels predict accelerated grey matter loss in the pre-frontal cortex. Thus, it may be that, in future, targeted interventions to prevent grey matter loss may also aid in the prevention of psychosis. 

Further reading

• Anticevic A et al. (2015) Association of thalamic dysconnectivity and conversion to psychosis in youth and young adults at elevated clinical risk. JAMA Psychiatry 72;882-891.
• Braff DL et al. (2008) Advances in endophenotyping schizophrenia.World Psychiatry 7;11-18.
• Cannon TD et al. (2016) Brain biomarkers of vulnerability and progression to psychosis. Schizophrenia Bulletin 42; Suppl1:S127-132.
• Greenwood TA et al. (2012) Association Analysis of 94 Candidate Genes and Schizophrenia-Related Endophenotypes. PLoS ONE 7(1):e29630.
• Greenwood TA et al. (2016) Genetic assessment of additional endophenotypes from the Consortium on the Genetics of Schizophrenia family study. Schizophrenia Research 170;30-40.