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Phenotypic heterogeneity is a major barrier to understanding the genetic architecture underlying schizophrenia. Incorporating endophenotypes is one way to reduce heterogeneity and facilitate more powerful genetic analysis. Candidate endophenotypes require systematic assessment against endophenotype criteria, and a ranking of their potential utility for genetic analysis. In this study we assess 20 cognitive and personality measures in a sample of 127 families with at least 2 cases of schizophrenia per family (n = 535) plus a set of 30 control families (n = 121) against 4 endophenotype criteria: (a) be associated with the illness but not be a part of its diagnosis, (b) be heritable, (c) co-segregate with the illness in families, and (d) be found in unaffected relatives at a higher rate than in the general population. The endophenotype ranking score (endophenotype ranking variable [ERV]) was used to rank candidate endophenotypes based on their heritability and genetic correlation with schizophrenia. Finally, we used factor analysis to explore latent factors underlying the cognitive and personality measures. Evidence for personality measures as endophenotypes was at least equivalent to that of the cognitive measures. Factor analysis indicated that personality and cognitive traits contribute to independent latent dimensions. The results suggest for this first time that a number of cognitive and personality measures are independent and informative endophenotypes. Use of these endophenotypes in genetic studies will likely improve power and facilitate novel aetiological insights.

Background: Despite growing research, it remains unclear if cannabis use is associated with additive cognitive impairment in people with psychotic illness and whether exposure in early adolescence is associated with poorer cognitive performance in adulthood., Methods: This cross-sectional study of a nationally representative sample of 1199 adults with psychotic illness compared current cognition (digit symbol coding) of 297 current users of cannabis (used in the past year), 460 past users (used previously but not in the past year) and 442 non-users (never used). Multiple logistic regression was used to examine whether cognitive performance of cannabis-user groups varied by exposure age and diagnosis (non-affective/affective psychoses)., Results: Unadjusted analysis showed current cannabis users had significantly higher odds of impaired cognitive function compared to non-users (odds ratio=1.52, 95%CI=1.04-2.22). After adjusting for potential confounders, differences between the three groups were not significant. Exposure age was not significant in adjusted analysis. In participants with nonaffective psychoses, cognitive ability of current cannabis users did not differ from non-users. However, in participants with affective psychoses, using cannabis in the last year was a significant predictor of impaired cognitive function (odds ratio=2.25, 95%CI=1.05-4.84)., Conclusion: Among people with psychotic illness, there was no significant difference in cognitive function between current, past and non-users of cannabis. However, when we compared cognitive performance of the three cannabis groups by diagnostic grouping, current cannabis use had a significant negative relationship with cognitive function in people with affective psychoses, but not in those with non-affective psychoses. This finding requires replication and further investigation., (Copyright © 2017 Elsevier B.V. All rights reserved.)

We used Bayesian cognitive modelling to identify the underlying causes of apparent inhibitory deficits in the stop-signal paradigm. The analysis was applied to stop-signal data reported by Badcock et al. (Psychological Medicine 32: 87-297, 2002) and Hughes et al. (Biological Psychology 89: 220-231, 2012), where schizophrenia patients and control participants made rapid choice responses, but on some trials were signalled to stop their ongoing response. Previous research has assumed an inhibitory deficit in schizophrenia, because estimates of the mean time taken to react to the stop signal are longer in patients than controls. We showed that these longer estimates are partly due to failing to react to the stop signal ("trigger failures") and partly due to a slower initiation of inhibition, implicating a failure of attention rather than a deficit in the inhibitory process itself. Correlations between the probability of trigger failures and event-related potentials reported by Hughes et al. are interpreted as supporting the attentional account of inhibitory deficits. Our results, and those of Matzke et al. (2016), who report that controls also display a substantial although lower trigger-failure rate, indicate that attentional factors need to be taken into account when interpreting results from the stop-signal paradigm.

Background: We aimed to examine the association between lifetime cannabis use and estimates of both premorbid and current cognitive function in psychotic disorders in an Australian cohort., Methods: In an Australian multicenter cohort, 1237 participants with an established ICD-10 diagnosis of psychotic disorder were categorised according to history of lifetime cannabis use (non-users, n=354; cannabis users, n=221; cannabis dependency, n=662). Groups were analyzed according to available indices of cognitive ability: the National Adult Reading Test - Revised (NART-R) for ability prior to illness onset; and the Digit Symbol Coding Test (DSCT) for current ability. Two-way analysis of variance was conducted without any covariate, followed by a two-way analysis of covariance (using age, age at onset of psychiatric illness, premorbid IQ and the Socio-Economic Index for Areas (SEIFA) rankings)., Results: Whilst there appeared to be a significant association between cannabis use and mean DSCT (higher DSCT scores in cannabis using groups) F(2,1080)=9.478, p<0.001, η2=0.017), once covariates were used in the analysis there were no significant differences between groups in mean DSCT scores (F(2,1011)=0.929, p=0.395, η2=0.002). Similarly there were no differences between groups in mean NART scores once, age, age at illness onset and SEIFA rankings were used as covariates (F(2,1032)=1.617, p=0.199, η2=0.003)., Conclusions: Confounding variables underpin the association between cannabis use and cognitive function in psychotic disorders. Taken together, it would appear that cannabis use or dependence has no additive effect on cognitive dysfunction in these disorders., (Crown Copyright © 2015. Published by Elsevier B.V. All rights reserved.)

Our previous neurocognitive studies of schizophrenia outlined two clusters of affected subjects--cognitively spared (CS) and cognitive deficit (CD), the latter's characteristics pointing to developmental origins and impaired synaptic plasticity. Here we investigate the contribution of polymorphisms in major regulators of these processes to susceptibility to schizophrenia and to CD in patients. We examine variation in genes encoding proteins at the gateway of Reelin signaling: ligands RELN and APOE, their common receptors APOER2 and VLDLR, and adaptor DAB1. Association analysis with disease outcome and cognitive performance in the Western Australian Family Study of Schizophrenia (WAFSS) was followed by replication analysis in the Australian Schizophrenia Research Bank (ASRB) and in the Health in Men Study (HIMS) of normal aging males. In the WAFSS sample, we observed significant association of APOE, APOER2, VLDLR, and DAB1 SNPs with disease outcome in the case-control and CD-control datasets, and with pre-morbid intelligence and verbal memory in cases. HIMS replication analysis supported rs439401 (APOE regulatory region), and rs2297660 and rs3737983 (APOER2), with an effect on memory performance in normal aging subjects consistent with the findings in schizophrenia cases. APOER2 gene expression analysis revealed lower transcript levels in lymphoblastoid cells from cognitively impaired schizophrenia patients of the alternatively spliced exon 19, mediating Reelin signaling and synaptic plasticity in the adult brain. ASRB replication analysis produced marginally significant results, possibly reflecting a recruitment strategy biased toward CS patients. The data suggest a contribution of neurodevelopmental/synaptic plasticity genes to cognitive impairment in schizophrenia., (Copyright © 2012 Wiley Periodicals, Inc.)

Objective: There is a dearth of longitudinal data on outcomes in prevalent cases of psychotic illness across a range of ages and levels of chronicity. Our aim was to describe changes over time in mental and physical health outcomes, as well as patterns of service utilisation that may have influenced outcomes, in a representative prevalence sample of 641 Western Australians with a psychotic illness who, at Wave 1, were part of the National Survey of High Impact Psychosis. Methods: In Wave 1 (2010, 2012), a two-phase design was employed to ensure representativeness: Phase 1 psychosis screening took place in public mental health and non-government organisation services, while, in Phase 2, a randomised sample was interviewed. In Wave 2, 380/641 (59%) of participants were re-interviewed, with interviews staggered between 2013 and 2016 (follow-up time: 2.3–5.6 years). Data collection covered mental and physical health, functioning, cognition, social circumstances and service utilisation. Mental health outcomes were categorised as symptomatic, functional and personal recovery. Physical health outcomes covered metabolic syndrome and its component criteria. Results: In mental health, there were encouraging improvements in symptom profiles, variable change in functional recovery and some positive findings for personal recovery, but not quality of life. Participants ranked physical health second among challenges. Metabolic syndrome had increased significantly. While treatment for underlying cardiovascular risk conditions had improved, rates of intervention were still very low. More people were accessing general practices and more frequently, but there were sharp and significant declines in access to community rehabilitation, psychosocial interventions and case management. Conclusion: Although we observed some positive outcomes over time, the sharp decline in access to evidence-based interventions such as community rehabilitation, psychosocial interventions and case management is of great concern and augurs poorly for recovery-oriented practice. Changes in service utilisation appear to have influenced the patterns found. [ABSTRACT FROM AUTHOR]

Cognitive impairment is a core feature of schizophrenia and impacts negatively the functioning of affected individuals. Cognitive decline correlates with aging, and is the primary cause of loss of independence and reduced quality of life. The klotho gene is a key modulator of aging, with expression deficiency resulting in premature aging, while overexpression extends lifespan and enhances cognition. A haplotype and functional human variant of the gene, KL-VS, increases expression and promotes longevity. KL-VS heterozygosity is associated with enhanced cognition and a larger volume of the right dorsolateral prefrontal cortex, a region involved in planning and decision-making, which is especially susceptible to shrinkage with age. We examined the effect of KL-VS heterozygosity on cognition in 497 schizophrenia patients and 316 healthy controls from the Western Australian Family Study of Schizophrenia (WAFSS) who had been comprehensively characterised by neurocognitive tests and classified into cognitively deficient (CD) and cognitively “spared” (CS) clusters. An older, cognitively normal population sample from the Health in Men Study (HIMS) was included to allow assessment of heterozygosity and memory in aged individuals. We show that heterozygosity is associated with better learning and memory in the younger WAFSS healthy controls but not in the aging HIMS sample. However, in schizophrenia patients, KL-VS has a selective effect on memory, with heterozygotes in CD and CS clusters performing worse than non-carriers. This effect was significant and more severe in the CD cluster, reinforcing the utility of subtyping patients into CD and CS clusters that may differ in their genetic underpinnings. [ABSTRACT FROM AUTHOR]

Background: Loneliness involves subjective, rather than objective, social isolation and has a range of negative effects on mental and physical functioning. The purpose of this study was to examine the prevalence of loneliness in psychotic disorders and its association with symptoms and cognitive performance.Method: Data were drawn from the second Australian National Survey of Psychosis and comprised responses from 1642 participants with an International Classification of Diseases 10 diagnosis of psychotic disorder who had completed a semi-structured interview of symptoms and social functioning (including loneliness), along with standardized assessments of current (digit symbol coding; DSC) and premorbid (National Adult Reading Test) cognitive ability. We examined the prevalence of loneliness across the diagnostic categories of psychosis, and its association with psychotic and non-psychotic symptoms and digit symbol coding scores.Results: The prevalence of loneliness was high, ranging from 74.75% in participants with delusional disorders to 93.8% in depressive psychosis, and was significantly higher than in the general population. Loneliness was also significantly associated with anhedonia and subjective thought disorder. Participants feeling socially isolated/lonely for company had significantly lower DSC scores than those who only felt lonely occasionally. Unexpectedly, participants who reported not feeling lonely had the lowest DSC scores.Conclusions: Loneliness is common across all psychotic disorders, particularly in depressive psychosis. It is specifically associated with ongoing loss of pleasure and disordered thoughts as well as impairment in current cognitive functioning. However, poor cognitive functioning is not inevitably associated with loneliness. Implications for personalized treatment of psychosis are discussed. [ABSTRACT FROM AUTHOR]

Abstract: The continuum model of psychosis has been extremely influential. It assumes that psychotic symptoms, such as auditory verbal hallucinations (AVH), are not limited to patients with psychosis but also occur in healthy, non-clinical individuals – suggesting similar mechanisms of origin. Recent debate surrounding this model has highlighted certain differences, as well as similarities, in the phenomenology of AVH in clinical and non-clinical populations. These findings imply that there may, in fact, be only partial overlap of the mechanism(s) involved in generating AVH in these groups. We review evidence of continuity or similarity, and dissimilarity, in cognitive, and related neural processes, underlying AVH in clinical and non-clinical samples. The results reveal some shared (intrusive cognitions, inhibitory deficits) and some distinct (aspects of source memory and cerebral lateralization) mechanisms in these groups. The evidence, therefore, supports both continuous and categorical models of positive psychotic symptoms. The review considers potential risks of uncritical acceptance of the continuum model and highlights some important methodological issues for future research. [Copyright &y& Elsevier]

Abstract: Difficulties binding together information in memory have often been reported in individuals with schizophrenia, and have been linked with auditory hallucinations and the predisposition to hallucinate in particular. However, some inconsistencies remain. For example, we previously examined binding of two external sources (voice and location) in hallucination-prone individuals and found no evidence of a binding deficit using a working memory task that involved automatic binding. Consequently, the current study examined both automatic and intentional binding. The Launay-Slade Hallucination Scale-Revised (LSHS-R) was administered to 559 undergraduates from which high (25) and low (25) scorers were drawn. The binding tasks assessed either automatic or intentional binding of voice and location features. The results showed no significant differences between high and low hallucination-prone individuals in binding these two external sources of information, regardless of the type of binding (automatic or intentional) assessed. Furthermore, hallucination-prone individuals demonstrated no difficulties recognising individual features of voice identity or location. These findings suggest that some memory deficits may emerge only as psychosis fully develops. [Copyright &y& Elsevier]

Abstract: Patients with schizophrenia and current auditory hallucinations exhibit a combination of deficits in context binding and intentional inhibition. Hallucinations also occur in the general population suggesting an underlying continuity of causal mechanisms, however, these experiences may also differ (e.g., in frequency), indicating some differences in aetiology. The aim of this study was to examine the frequency of hallucinatory experiences in healthy young adults and to assess whether difficulties in context binding characterize individuals highly predisposed to hallucinations. A modified version of the Launay–Slade hallucination scale-revised, including an assessment of the frequency of hallucination experiences, was completed by 615 undergraduates from which sub-samples of high (n =25) and low (n =27) scorers were drawn. Context memory ability was assessed using a voice–location binding task. The results showed that the frequency of hallucinations in high LSHS-R scorers was much less than that previously reported for individuals with schizophrenia. Furthermore, no group differences in context memory binding were observed, nor any association between hallucination frequency and context binding difficulties. The continuity model of hallucinations may overlook some important differences in hallucinatory experiences in the general population versus psychosis. [Copyright &y& Elsevier]

Abstract: Background: Visuospatial working memory is not a unitary sketch pad but comprises independent dimensions of target distance and direction and at least two levels of detail (fine-grained and category level). The aim of this study was to examine these multiple aspects of encoding in patients with schizophrenia using a modified delayed response task. Method: 42 patients with schizophrenia and 48 healthy controls pointed, as accurately as possible from a fixed starting position, to the visual location of target stimuli presented to a touch-sensitive screen. An adaptive staircase procedure was used to equate stimulus duration for each individual. Encoding accuracy and maintenance of distance (mm) and direction (°) information was examined following a 0-second (immediate) or 4-second (unfilled) delay. Analyses utilized both absolute (unsigned) and signed data. Results: The results showed that the average duration required to detect a target was significantly longer in patients than controls. When stimulus duration was equated, (a) the absolute accuracy of distance and direction responses was not significantly different between groups at 0-second delay but was significantly reduced at 4-second delay in patients with schizophrenia, and (b) signed direction errors at 4-second delay were significantly different between groups at stimulus angles greater than 90°. Conclusions: The findings challenge previous suggestions of deficits in fine-grained encoding of spatial information in schizophrenia but confirm a difficulty maintaining both direction and distance details in working memory. Imprecision in spatial memory in schizophrenia also introduced greater bias from category level (prior) representations, especially in left hemi-space. [Copyright &y& Elsevier]

There is a growing literature describing a subgroup of “high-functioning” people with schizophrenia who show preserved intellectual ability (IQ). A detailed characterisation of the cognitive abilities of this group may be important in targeting appropriate treatment, management and services for patients with schizophrenia. It is a widely held belief that variation in cognitive processing speed is the basis of individual differences in intelligence. The main objective of this study was to identify subgroups of schizophrenia patients with preserved (N=45), deteriorated (N=47) and compromised (N=17) intellect in order to study whether these subgroups differ in specific cognitive abilities (e.g. executive functions) or in general cognitive processing speed, as measured with an inspection time (IT) task. The patients who displayed an average estimated premorbid IQ, with no evidence of IQ decline (premorbid-current IQ difference <10 points), were found to show better performance on measures of executive function (continuous performance task, verbal fluency) compared with patients in the deteriorated and compromised subgroups. Nevertheless, this represented significantly impaired performance relative to healthy controls. In contrast, the average inspection times of patients with preserved IQ were as slow as those obtained in the deteriorated or compromised groups, indicating that high functioning patients are impaired in terms of cognitive processing speed. Furthermore, the average IT for all schizophrenia groups was significantly slower than that of healthy controls. These findings suggest that high functioning patients with schizophrenia exhibit enduring cognitive difficulties that may impact on their ability to benefit from rehabilitation interventions. [Copyright &y& Elsevier]

The authors reflect on auditory hallucination (AH) mechanics. They mention its phenomenological diversity and involvement in biopsychological process. They note its association with schizophrenia, emotional process and attention. They also point out the neural processing theme indicating reduced feedback to speech sounds among voice listeners.

Deficits in action (verb) fluency have previously been reported in schizophrenia spectrum disorders. The degree to which this reflects difficulties generating verbs in different semantic categories is unknown. Here, action fluency responses of 46 patients with schizophrenia spectrum disorders and 76 healthy controls were classified as action or mental state verbs, using well-established taxonomies. The word length, frequency, age of acquisition, valence and concreteness of the verbs produced were also examined. Participants also completed measures of cognitive function, and clinical symptoms. Independent inter-rater agreement of semantic categorization was high. The percentage of action verbs produced was significantly lower in patients than controls, whilst the percentage of mental state verbs produced did not differ. Patients’ action verbs were: significantly less concrete; positively correlated with memory and intelligence; and negatively correlated with interpersonal symptoms. Impaired action verb, but intact mental state verb generation is consistent with the neural separability of these processes. [ABSTRACT FROM AUTHOR]