Vaughn J. Carr

Childhood adversity in schizophrenia: a systematic meta-analysis

BACKGROUNDnChildhood adversity is a putative risk factor for schizophrenia, although evidence supporting this suggestion is inconsistent and controversial. The aim of this review was to pool and quality assess the current evidence pertaining to childhood adversity in people with schizophrenia compared to other psychiatric disorders and to non-psychiatric controls.nnnMETHODnIncluded were case-control, cohort and cross-sectional studies. Medline, EMBASE and PsycINFO databases were searched. Study reporting was assessed using the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) checklist and pooled evidence quality was assessed by the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach.nnnRESULTSnTwenty-five studies met inclusion criteria. Moderate to high quality evidence suggests increased rates of childhood adversity in schizophrenia compared to controls [odds ratio (OR) 3.60, p < 0.00001]. Increased childhood adversity was also reported in schizophrenia compared to anxiety disorders (OR 2.54, p = 0.007), although the effect was not significant in the subgroup analysis of five studies assessing only sexual abuse. No differences in rates of childhood adversity were found between schizophrenia and affective psychosis, depression and personality disorders whereas decreased rates of childhood adversity were found in schizophrenia relative to dissociative disorders and post-traumatic stress disorder (OR 0.03, p < 0.0001).nnnCONCLUSIONSnThis is the first meta-analysis to report a medium to large effect of childhood adversity in people with schizophrenia and to assess specificity for schizophrenia. Further research is required that incorporates longitudinal design and other potentially causal variables to assess additive and/or interactive effects.

Adjunctive raloxifene treatment improves attention and memory in men and women with schizophrenia

There is increasing clinical and molecular evidence for the role of hormones and specifically estrogen and its receptor in schizophrenia. A selective estrogen receptor modulator, raloxifene, stimulates estrogen-like activity in brain and can improve cognition in older adults. The present study tested the extent to which adjunctive raloxifene treatment improved cognition and reduced symptoms in young to middle-age men and women with schizophrenia. Ninety-eight patients with a diagnosis of schizophrenia or schizoaffective disorder were recruited into a dual-site, thirteen-week, randomized, double-blind, placebo-controlled, crossover trial of adjunctive raloxifene treatment in addition to their usual antipsychotic medications. Symptom severity and cognition in the domains of working memory, attention/processing speed, language and verbal memory were assessed at baseline, 6 and 13 weeks. Analyses of the initial 6-week phase of the study using a parallel groups design (with 39 patients receiving placebo and 40 receiving raloxifene) revealed that participants receiving adjunctive raloxifene treatment showed significant improvement relative to placebo in memory and attention/processing speed. There was no reduction in symptom severity with treatment compared with placebo. There were significant carryover effects, suggesting some cognitive benefits are sustained even after raloxifene withdrawal. Analysis of the 13-week crossover data revealed significant improvement with raloxifene only in attention/processing speed. This is the first study to show that daily, oral adjunctive raloxifene treatment at 120 mg per day has beneficial effects on attention/processing speed and memory for both men and women with schizophrenia. Thus, raloxifene may be useful as an adjunctive treatment for cognitive deficits associated with schizophrenia.

Pervasive influence of maternal and paternal criminal offending on early childhood development: A population data linkage study

Background Parental criminal offending is an established risk factor for offending among offspring, but little evidence is available indicating the impact of offending on early childhood functioning. We used data from a large Australian population cohort to determine associations between exposure to parental offending and a range of developmental outcomes at age 5 years. Method Multi-generation data in 66 477 children and their parents from the New South Wales Child Development Study were combined using data linkage. Logistic and multinomial regressions tested associations between any and violent offending histories of parents (fathers, mothers, or both parents) obtained from official records, and multiple measures of early childhood developmental functioning (social, emotional–behavioural, cognitive, communication and physical domains) obtained from the teacher-reported 2009 Australian Early Development Census. Results Parental offending conferred significantly increased risk of vulnerability on all domains, particularly the cognitive domain. Greater risk magnitudes were observed for offending by both parents and by mothers than by fathers, and for violent than for any offending. For all parental offending exposures, vulnerability on multiple domains (where medium to large effects were observed) was more likely than on a single domain (small to medium effects). Relationships remained significant and of comparable magnitude following adjustment for sociodemographic covariates. Conclusions The effect of parental offending on early childhood developmental outcomes is pervasive, with the strongest effects on functioning apparent when both parents engage in violent offending. Supporting affected families in early childhood might mitigate both early developmental vulnerability and the propensity for later delinquency among these offspring.

Effects of maltreatment and parental schizophrenia spectrum disorders on early childhood social-emotional functioning: a population record linkage study

Aims. Childhood maltreatment and a family history of a schizophrenia spectrum disorder (SSD) are each associated with social-emotional dysfunction in childhood. Both are also strong risk factors for adult SSDs, and social-emotional dysfunction in childhood may be an antecedent of these disorders. We used data from a large Australian population cohort to determine the independent and moderating effects of maltreatment and parental SSDs on early childhood social-emotional functioning. Methods. The New South Wales Child Development Study combines intergenerational multi-agency data using record linkage methods. Multiple measures of social-emotional functioning (social competency, prosocial/helping behaviour, anxious/fearful behaviour; aggressive behaviour, and hyperactivity/inattention) on 69 116 kindergarten children (age ~5 years) were linked with government records of child maltreatment and parental presentations to health services for SSD. Multivariable analyses investigated the association between maltreatment and social-emotional functioning, adjusting for demographic variables and parental SSD history, in the population sample and in sub-cohorts exposed and not exposed to parental SSD history. We also examined the association of parental SSD history and social-emotional functioning, adjusting for demographic variables and maltreatment. Results. Medium-sized associations were identified between maltreatment and poor social competency, aggressive behaviour and hyperactivity/inattention; small associations were revealed between maltreatment and poor prosocial/helping and anxious/fearful behaviours. These associations did not differ greatly when adjusted for parental SSD, and were greater in magnitude among children with no history of parental SSD. Small associations between parental SSD and poor social-emotional functioning remained after adjusting for demographic variables and maltreatment. Conclusions. Childhood maltreatment and history of parental SSD are associated independently with poor early childhood social-emotional functioning, with the impact of exposure to maltreatment on social-emotional functioning in early childhood of greater magnitude than that observed for parental SSDs. The impact of maltreatment was reduced in the context of parental SSDs. The influence of parental SSDs on later outcomes of maltreated children may become more apparent during adolescence and young adulthood when overt symptoms of SSD are likely to emerge. Early intervention to strengthen childhood social-emotional functioning might mitigate the impact of maltreatment, and potentially also avert future psychopathology.

F193. DYSREGULATION OF RETINOID SIGNALLING IN SCHIZOPHRENIA OBSERVED IN WHOLE GENOME SEQUENCE ANALYSIS

Abstract Background Retinoic acid (RA) is intrinsically linked to neurodevelopment and has been implicated in schizophrenia (SZ). This is supported by preliminary trials of a retinoid receptor agonist, Bexarotene, as an adjuvant and the association of five common variants in proximity to members of this pathway at genome wide significance. In addition to these high frequency variants with small effect size, we suspect that this pathway is also affected by rare variants with much higher impact. We aimed to examine the burden of variants in retinoid loci in schizophrenia along with its potential consequences for clinical practice. Methods Whole genome sequencing was performed on SZ cases (N=331) and non-psychiatric controls (N=167). Cases were further clustered by cognitive measures to derive the cognitive deficit (CD; N=166) and cognitively spared (CS; N=165) subtypes. Disease and subtype associated genomic variation was then analysed in a panel of 129 genes selected for involvement in RA biology (Molecular Signatures Database). Rare variation was aggregated at the gene level using the optimal unified sequence kernel association test (SKAT-O). Clinical metadata was further examined for each case with a rare putative high impact loss of function variant in a RA panel gene predicted using SnpEff. The rare variant burden on target genes of RA receptor binding in SZ was investigated by logistic regression of variants mapped to consensus 5 base pair spaced direct repeat (DR5) retinoic acid response element (RARE) motifs. Results Gene level rare variant association uncovered suggestive associations with SZ (P < 0.01) for three retinoid genes – RBP3, ADH1C and RPE65. In addition, a stronger signal was detected overall for CD cases implicating four additional genes including the RA receptors RARB (P = 1.1 x 10–3) and RARG (P = 9.2 x 10–3). SZ patients with a rare high impact genotype predicted in a RA panel gene were more likely to have serious symptomology as defined by a global assessment of functioning (GAF) score below 50, P = 7.1 x 10–3 (Two-Tailed Fisher’s Exact Test). We also found evidence of an increased burden of rare variants within predicted DR5-RARE in SZ (P = 0.017, odds ratio [OR] = 1.094, 95% confidence interval [CI] = 1.023- 1.186), however, there was no significant difference between the cognitive subtypes (CD/CS, P = 0.8, OR = 1.002, 95% CI = 0.961–1.045). Discussion Our findings suggest that RA mediated control of gene expression is heterogeneously disrupted in SZ by rare variants in DR5-RARE motifs. Strong signals in the context of our sample size further support the possibility of enrichment of rare loci in genes involved with RA biology, particularly in CD cases with impaired cognition. Moreover, we identified a subset of patients with likely high effect size genotypes in the RA pathway. Future work will examine whether these high-risk patients would benefit from retinoid based pharmacological intervention.

A progress report on the Australian Schizophrenia Research Bank

In 2007 the Australian Schizophrenia Research Bank was officially launched and a recruitment campaign commenced to achieve an initial sample of 2,000 cases of schizophrenia and2,000 healthy controls for a nationwide genetic epidemiology study of schizophrenia. The study involves scientific collaborators in four States and is funded through a NHMRC Enabling Grant, philanthropic sources and the resources of the Schizophrenia Research Institute. All participants undergo a comprehensive clinical assessment using a structured diagnostic interview and symptom ratings, a neuropsychological test battery and structural MRI scanning; blood is taken for later genetic studies. This paper presents a limited range of data on the first participants recruited (N322 at the time of writing, 187 cases and135 controls) one third of whom have had MRI scans. Some of the challenges involved in a large-scale initiative of this kind are discussed, including consensus protocol development; quality control issues; staff recruitment and training; participant sampling and assessment ; governance and access policies and systems; data storage, management and transfer; communications and operational management challenges. All of these factors are crucial for ensuring the integrity of the information held in the Bank. By linking reliable and valid clinical, cognitive, neuroanatomical and genetic information in a large sample of cases and controls, the Bank has the potential to subdivide the schizophrenia phenotype and identify aetiologically significant subgroups with characteristic genetic, neuropsychological, and neuroimaging profiles.A40 AUSTRALIAN AND NEW ZEALAND JOURNAL OF PSYCHIATRY (2008) 42 (Suppl. 2).Background: Psychotic-Like Experiences (PLEs) are predictive of psychosis, yet are also commonly reported in community studies. It remains unclear why these same symptoms are endorsed by both people at imminent risk for psychotic disorder and also among people with no symptomatology or functional impairment. We hypothesised that PLEs, as measured through questionnaire, would be only moderately related to interview ratings of PLEs. Further, we hypothesise that there will be a stronger relation between these methods in clinical vs. community samples. Methods: Two distinct samples were used in the present study: (1) 150 young help-seekers (mean age 17.8 years) referred to a mental health service; (2) 651 adolescents (mean age 15.8 years) recruited from secondary schools across Melbourne, Australia. InterviewPLEs were assessed by the Comprehensive Assessment of At-Risk Mental States (CAARMS) and questionnaire-PLEs by the Community Assessment of Psychic Experiences (CAPE). Results: Self-report PLEs were reported by the majority of participants in both samples (Community: 99.1%, Help-Seekers: 98.6%). In comparison, interview-rated PLEs were endorsed less frequently (Community: 46.2%, Help-Seekers: 62%). There was a moderate relationship between interviewand self-report PLEs among help-seekers (r .4 .6). However, there was a weaker relationship in the community sample (r .2 .4). Discussion: Self-reported and interview-rated PLEs showed a differential relationship across the distinct samples investigated in the present study. It may be that healthy young people are unfamiliar with the constructs tested in measures such as the CAPE and may frequently misinterpret questions, leading to artificially inflated prevalences. STRESS AND HPA AXIS FUNCTIONING IN FIRST-EPISODE PSYCHOSIS: NEUROCOGNITIVE EFFECTS ON RELATIONAL MEMORY

An overview of the Australian schizophrenia research bank: Linking brain function and structure with genetics in a large sample of schizophrenia cases and controls

Introduction: The study of narcissism is under-represented in clinical research. However, there is evidence that narcissism is a dimensional disorder, with sub-clinical levels being found in nonclinical populations In addition, despite the emerging consensus that two distinct facets of narcissism exist an overt (grandiose) facet and a covert (vulnerable) facet with different characteristics, it remains unclear whether they are two separate personality subtypes, two ends of an adjustment continuum, or two co-existing facets manifesting in different situations. The present two studies were designed to examine these propositions in non-clinical samples, by investigating the structure of overt and covert narcissism in terms of basic personality profiles, and explicit and implicit self-esteem. Method: Participants completed a battery of online inventories and tasks assessing overt narcissism, covert narcissism, the Five Factor Model of personality, and explicit self-esteem and implicit selfesteem. Correlational and multiple regression analyses were used to examine the relationships between overt-covert narcissism and the constructs of interest. Results: In both studies overt and covert narcissism had different patterns of predictors. Overt narcissism was best predicted by high Extraversion, low Agreeableness, high Openness to Experience and high Conscientiousness, while covert narcissism was best predicted by high Neuroticism and low Agreeableness. Overt narcissism was associated with high explicit self-esteem and low implicit positive self-esteem, whereas covert narcissism was associated with high implicit positive self-esteem and low explicit self-esteem. Conclusions: The results support the view that overt and covert narcissism are distinct subtypes that are associated with different personality and self-esteem profiles, rather than two ends of a continuum or co-existing facades manifesting in different situations. The implications of the findings are discussed. THE INFLUENCE OF THE LEVEL OF MEASUREMENT ON THE STRUCTURE OF PERSONALITY DISORDERSIntroduction: This paper reports on the development of a national recruitment and clinical assessment strategy by the Australian Schizophrenia Research Bank (ASRB). The aim of this strategy is to ensure a representative sample of people with schizophrenia and to collect comprehensive, cross-referenced clinical, cognitive, genetic, brain imaging and linked data. Method: The ASRB recruitment targets are 2000 people with schizophrenia and 2000 healthy, non-psychiatric controls. Using a three pronged approach, schizophrenia subjects will be recruited from various settings. To recruit people in the community, a successful TV and radio community service advertisement campaign was developed and a national 1800 telephone number established. The assessment battery includes the Diagnostic Interview for Psychosis (DIP: Castle et al, 2005), Neurological Evaluation Scale (Buchanan & Heinrichs, 1989), Wechsler Test of Adult Reading (WTAR-Wechsler, 2001), Wechsler Abbreviated Scale of Intelligence (WASI-Wechsler, 1999), Repeatable Battery for Assessment of Neuropsychological Status (RBANS Randolph et al, 1998), Letter Number Sequencing (Wechsler, 1997), Controlled Oral Word Association Test (Spreen & Benton, 1969), Global Assessment of Functioning (GAF-American Psychiatric Association, 2000), and the Schizotypal Personality Questionnaire (Raine et al., 1991). In addition, a blood sample and structural MRI scan are collected. Results: Over 2000 people have registered with the ASRB using the 1800 number. A proportion of these people have been assessed using the ASRB assessment battery. Conclusion: The ASRB is the first Australian research facility to develop a national recruitment and clinical assessment strategy in schizophrenia.