April Hargreaves

There is compelling evidence for the role of copy number variants (CNVs) in schizophrenia susceptibility, and it has been estimated that up to 2-3% of schizophrenia cases may carry rare CNVs. Despite evidence that these events are associated with an increased risk across categorical neurodevelopmental disorders, there is limited understanding of the impact of CNVs on the core features of disorders like schizophrenia. Our objective was to evaluate associations between rare CNVs in differentially brain expressed (BE) genes and the core features and clinical correlates of schizophrenia. The sample included 386 cases of Irish ancestry with a diagnosis of schizophrenia, at least one rare CNV impacting any gene, and a core set of phenotypic measures. Statistically significant associations between deletions in differentially BE genes were found for family history of mental illness (decreased prevalence of all CNVs and deletions, unadjusted and adjusted) and for paternal age (increase in deletions only, unadjusted, among those with later ages at birth of patient). The strong effect of a lack of a family history on BE genes suggests that CNVs may comprise one pathway to schizophrenia, whereas a positive family history could index other genetic mechanisms that increase schizophrenia vulnerability. To our knowledge, this is the first investigation of the association between genome-wide CNVs and risk factors and sub-phenotypic features of schizophrenia beyond cognitive function.

Cognitive remediation (CR) has emerged as the treatment of choice for impaired cognition in psychosis. However, little is known about adherence rates and factors predicting adherence to CR, particularly in clinical settings where high-level therapist support is unavailable. This study aimed to establish adherence rates and examine variables predicting adherence to a computerized CR program for psychosis (with minimal support). Patients with psychosis (n = 61) participated in an 8-week CR program. Results showed 46% completed a meaningful amount of CR training. The fully adherent (>80% of the prescribed amount) and nonadherent groups differed where adherent participants had poorer working-memory and higher negative symptom scores. These findings suggest that approximately half of the sample were adherent to treatment despite minimal therapist support. Furthermore, higher cognitive deficits and negative symptoms did not impede adherence, and may have contributed to patients' mo...

Cognitive deficits are a core feature of schizophrenia and related psychotic disorders and are associated with decreased levels of functioning. Behavioural interventions have shown success in remediating these deficits; determining how best to maximise this benefit while minimising the cost is an important next step in optimising this intervention for clinical use. To examine the effects of a novel working-memory focused cognitive remediation (CR) training on cognitive difficulties based on internet delivery of training and weekly telephone support. Participants with a diagnosis of psychosis (n=56) underwent either 8weeks of CR (approximately 20h) or 8weeks of treatment as usual (TAU). General cognitive ability, working memory and episodic memory were measured both pre and post intervention for all participants. In addition to improvements on trained working memory tasks, CR training was associated with significant improvements in two tests of verbal episodic memory. No association ...

1. Schizophr Res. 2011 Feb;125(2-3):304-6. Epub 2010 Nov 26. A neuropsychological investigation of the genome wide associated schizophrenia risk variant NRGN rs12807809. Donohoe G, Walters J, Morris DW, Da Costa A, Rose E, Hargreaves A, Maher K, Hayes E, Giegling I, Hartmann AM, Möller HJ, Muglia P, Moskvina V, Owen MJ, O'Donovan MC, Gill M, Corvin A, Rujescu D. PMID: 21112188 [PubMed - indexed for MEDLINE]. Publication Types: Letter; Research Support, Non-US Gov't. MeSH Terms. ...

There is compelling evidence for the role of copy number variants (CNVs) in schizophrenia susceptibility, and it has been estimated that up to 2-3% of schizophrenia cases may carry rare CNVs. Despite evidence that these events are associated with an increased risk across categorical neurodevelopmental disorders, there is limited understanding of the impact of CNVs on the core features of disorders like schizophrenia. Our objective was to evaluate associations between rare CNVs in differentially brain expressed (BE) genes and the core features and clinical correlates of schizophrenia. The sample included 386 cases of Irish ancestry with a diagnosis of schizophrenia, at least one rare CNV impacting any gene, and a core set of phenotypic measures. Statistically significant associations between deletions in differentially BE genes were found for family history of mental illness (decreased prevalence of all CNVs and deletions, unadjusted and adjusted) and for paternal age (increase in deletions only, unadjusted, among those with later ages at birth of patient). The strong effect of a lack of a family history on BE genes suggests that CNVs may comprise one pathway to schizophrenia, whereas a positive family history could index other genetic mechanisms that increase schizophrenia vulnerability. To our knowledge, this is the first investigation of the association between genome-wide CNVs and risk factors and sub-phenotypic features of schizophrenia beyond cognitive function.

Schizophrenia is accompanied by significant impairment in psychosocial functioning, which is only partially explained by clinical symptom severity. Recently, these impairments have been strongly associated with deficits in neurocognition and social cognition. Although the Global Assessment of Function (GAF) scale remains the most widely used measure of psychosocial function in clinical practice, it is unclear whether this instrument is sensitive to changes in cognition, or merely provides a snapshot of symptom severity. To investigate this, we assessed whether variation in GAF score was explained by performance on measures of neurocognitive and social cognition, particularly after variation associated with symptom severity had been accounted for. 216 patients with schizophrenia were assessed using the GAF scale, two theory of mind tasks (the 'Hinting' task and 'Reading the Eyes in the Mind' task), and a neuropsychological battery sensitive to the areas of deficit typically seen in schizophrenia - IQ, episodic memory, working memory and attentional control. Using linear regression analysis, symptom severity explained 24% of the variance in GAF scores (F(3, 188) = 21.14, p<.001). While neuropsychological performance explained a further 4.7% of variation (r(2)change = .047, Fchange (1, 187) = 12.63, p<.001), social cognition did not explain any further variance in functioning (r(2)change = .006, Fchange (1, 186) = 1.63, p = .20). These data indicate that GAF scores are primarily sensitive to variation in clinical symptoms severity and not at all sensitive to variation in social cognition, an important determinant of real world outcome. Doing so highlights the need to supplement the measurement of psychosocial function using the GAF in clinical practice with functional measures that are more sensitive to deficits in social cognition.

The single nucleotide polymorphism rs10503253, located within the CUB and Sushi multiple domains-1 (CSMD1) gene on 8p23. 2, was recently identified as genome wide significant for schizophrenia, but is of unknown function. We investigated the neurocognitive effects of this CSMD1 variant in vivo in patients and healthy participants using behavioral and imaging measures of brain structure and function. We compared carriers and non-carriers of the risk 'A'allele on measures of neuropsychological ...