A comparison of trajectories of offending among people with psychotic disorders, other mental disorders and no mental disorders: Evidence from a whole-of-population birth cohort study.

BACKGROUND: Trajectory analysis has been used to study long-term offending patterns and identify offender subgroups, but few such studies have included people with psychotic disorders (PDs) and these have been restricted to adult offenders. AIMS: To compare offending trajectories among 10-26-year-olds with PDs with those with other mental disorders (OMDs) or none (NMD) and identify associated risk factors. METHODS: This is a record-linkage study of 184,147 people born in Western Australia (WA) 1983-1991, drawing on data from WA mental health information system, WA corrective services and other state-wide registers. Group-based trajectory modelling was used to identify offending trajectories. RESULTS: Four offender groups were identified in each mental health status group: G1-no/negligible offending; G2-early onset, adolescent, desisting by age 18; G3-early onset, low rate, offending into early adulthood; and G4-very early onset, high rate, peaking at age 17, continuing into early adulthood. The PDs group had the lowest proportion of individuals with no or negligible offending histories-84% compared with 88.5% in the OMDs group and 96.6% in the no mental disorder group. Within mental health status offender groups, the PDs group was characterised by early or very early onset offending persisting into adulthood, accounting for 5.4% and 3.7% of the group respectively (OMD: 3.8%, 1.5%; NMD: 1.0%, 0.5%). Gender, indigenous status, substance use problems, childhood abuse and parental offending were generally associated with trajectory group membership, although among those with PDs childhood abuse and parental offending were only significant in the early onset-life-course-persistent group. CONCLUSIONS: While most people with PDs never offend, some are disproportionately vulnerable from a particularly early age. If the offending subgroup is to be helped away from criminal justice involvement, interventions must be considered in childhood.

Genetic Overlap Profiles of Cognitive Ability in Psychotic and Affective Illnesses: A Multisite Study of Multiplex Pedigrees.

BACKGROUND: Cognitive impairment is a key feature of psychiatric illness, making cognition an important tool for exploring of the genetics of illness risk. It remains unclear which measures should be prioritized in pleiotropy-guided research. Here, we generate profiles of genetic overlap between psychotic and affective disorders and cognitive measures in Caucasian and Hispanic groups. METHODS: Data were from 4 samples of extended pedigrees (N = 3046). Coefficient of relationship analyses were used to estimate genetic overlap between illness risk and cognitive ability. Results were meta-analyzed. RESULTS: Psychosis was characterized by cognitive impairments on all measures with a generalized profile of genetic overlap. General cognitive ability shared greatest genetic overlap with psychosis risk (average endophenotype ranking value [ERV] across samples from a random-effects meta-analysis = 0.32), followed by verbal memory (ERV = 0.24), executive function (ERV = 0.22), and working memory (ERV = 0.21). For bipolar disorder, there was genetic overlap with processing speed (ERV = 0.05) and verbal memory (ERV = 0.11), but these were confined to select samples. Major depressive disorder was characterized by enhanced working and face memory performance, as reflected in significant genetic overlap in 2 samples. CONCLUSIONS: There is substantial genetic overlap between risk for psychosis and a range of cognitive abilities (including general intelligence). Most of these effects are largely stable across of ascertainment strategy and ethnicity. Genetic overlap between affective disorders and cognition, on the other hand, tends to be specific to ascertainment strategy, ethnicity, and cognitive test battery.

Genetic copy number variants, cognition and psychosis: a meta-analysis and a family study.

The burden of large and rare copy number genetic variants (CNVs) as well as certain specific CNVs increase the risk of developing schizophrenia. Several cognitive measures are purported schizophrenia endophenotypes and may represent an intermediate point between genetics and the illness. This paper investigates the influence of CNVs on cognition. We conducted a systematic review and meta-analysis of the literature exploring the effect of CNV burden on general intelligence. We included ten primary studies with a total of 18,847 participants and found no evidence of association. In a new psychosis family study, we investigated the effects of CNVs on specific cognitive abilities. We examined the burden of large and rare CNVs (>200 kb, <1% MAF) as well as known schizophrenia-associated CNVs in patients with psychotic disorders, their unaffected relatives and controls (N = 3428) from the Psychosis Endophenotypes International Consortium (PEIC). The carriers of specific schizophrenia-associated CNVs showed poorer performance than non-carriers in immediate (P = 0.0036) and delayed (P = 0.0115) verbal recall. We found suggestive evidence that carriers of schizophrenia-associated CNVs had poorer block design performance (P = 0.0307). We do not find any association between CNV burden and cognition. Our findings show that the known high-risk CNVs are not only associated with schizophrenia and other neurodevelopmental disorders, but are also a contributing factor to impairment in cognitive domains such as memory and perceptual reasoning, and act as intermediate biomarkers of disease risk.

Mental health recovery and physical health outcomes in psychotic illness: Longitudinal data from the Western Australian survey of high impact psychosis catchments.

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.

Use of the Communication Checklist - Self Report (Cc-Sr) in Schizophrenia: Language Impairments Correlate with Poor Premorbid Social Adjustment.

BACKGROUND: The present study reports preliminary results from the multicentre project on the approbation of the Russian language version of the "The Communication Checklist-Self Report" (RL-CC-SR) and its first use in schizophrenia (SZ), aiming to evaluate the contribution of language disturbances in the pathogenesis of this heterogeneous disorder. SUBJECTS AND METHODS: The study evaluated patients' clinical state with the Diagnostic Interview for Psychoses (DIP), and assessed language and communication disturbances (LCD) with the RL-CC-SR in all participants (213 healthy controls (HC), 83 SZ patients, 31 SZ first-degree relatives). Data from the current sample of SZ (n=50), and HC (n=213) was analysed to calculate the relationships between LCD, social and clinical variables using descriptive statistics methods, T-test and Pearson's correlations (SPSS-26, 2019). RESULTS: The quotient scores (<6) and raw scores on all three CC-SR subscales demonstrated prominent LCD in SZ: (i) language structure (LS) (SZ:11.92±8.01, HC:7.54±5.91; p<0.001), (ii) pragmatic skills (PS) (SZ:11.30±10.07, HC:8.71±7.39; p=0.040), (iii) social engagement (SE) (SZ:31.94±11.76, HC:19.42±10.35; p<0.001). In SZ, Pearson correlations of LS scores were significant for the DIP-items Odd Speech (p=0.033), and Social Engagement - Blunted Affect (p=0.042). PS was related to early disease onset (p=0.027), poor premorbid work adjustment (p=0.003), along with LS (p=0.005), and was also linked to poor premorbid social adjustment (p=0.005). CONCLUSIONS: SZ patients are aware of their LCD at all levels of language structure, pragmatics, and nonverbal communication, but are unable to compensate. Disturbances of LS and PS in SZ patients relate to their poor social adjustment and functioning, and may prove to be associated with the primary negative symptoms domain of the disorder and its generally poor outcome.

Parsing components of risk of premature mortality in the children of mothers with severe mental illness.

INTRODUCTION: Children of mothers with severe mental illness are at increased risk of premature death including in infancy and early childhood. Importantly, these children are also more likely to be exposed to adverse socio-demographic risk factors and serious obstetric complications which, of themselves, may increase risk for childhood mortality. We examined mortality outcome at different ages up to 5 years taking account of these risks. METHOD: We used linked data across Western Australian whole-population psychiatric, inpatient, death, and midwives' registers to identify 15,486 births to mothers with severe mental illness and 452,459 births to mothers with no mental illness. Multivariable models were adjusted for exposure to adverse socio-demographic risk factors and serious obstetric complications. RESULTS: Overall risk of premature death was increased amongst children of mothers with severe mental illness (2.3%, 354 deaths) compared with children of mothers with no mental illness (1.4%, 6523 deaths); the same was true for specific risk of stillbirth, neonatal, post­neonatal and early childhood deaths. Risk was substantially attenuated after adjustment for adverse socio-demographic exposures, and further still after adjustment for exposure to serious obstetric complications. We observed no effects for the timing of maternal illness diagnosis. CONCLUSIONS: To minimise the risk of premature mortality in the children of mothers with severe mental illness, priority should be given to the prompt diagnosis of maternal mental illness with targeted delivery of high quality antenatal and psychiatric care, as well as social and structural supports for affected families that continue after birth.

Impact of substance use and other risk factor exposures on conviction rates by people with a psychotic illness and other mental disorders.

PURPOSE: To examine the impact of substance use and other risk factors on conviction rates in people with a psychotic illness (PI) and other mental disorders (OMD) compared to those with no mental illness (NMI). METHODS: This research is part of a longitudinal record-linked whole-population study of 467,945 children born in Western Australia (WA) between 1980 and 2001. This cohort was identified through linkages between the WA psychiatric case register, WA corrective services data and other state-wide registers. We assessed 184,147 individuals born during 1983-1991 to explore the impact of exposure to a variety of risk factors on conviction rates. RESULTS: People with PI and OMD had higher conviction rates than those with NMI, with unadjusted incidence rate ratios (IRR) of 3.98 (95% CI 3.67-4.32) for PI and 3.18 (95% CI 3.03-3.34) for OMD. Adjusting for substance use reduced the rates by 60% in PI and 30% in OMD: IRRs 1.59 (95% CI 1.45-1.74) and 2.24 (2.12-2.37), respectively. Minimal change was seen when adjusting for other potential risk factors (including socio-demographics, victimisation and parental offending), with adjusted IRRs 1.58 (95% CI 1.43-1.74) for PI and 1.90 (95% CI 1.80-2.02) for OMD. CONCLUSIONS: Our analysis shows people with a mental illness have higher rates of conviction than those with NMI. Substance use has a major impact on this rate. Results suggest the need for a greater investment in programs addressing the issue of comorbid substance use with a view to reduce the rate of convictions in this population.

Wnt receptor gene FZD1 was associated with schizophrenia in genome-wide SNP analysis of the Australian Schizophrenia Research Bank cohort.

OBJECTIVES: Large-scale genetic analysis of common variation in schizophrenia has been a powerful approach to understanding this complex but highly heritable psychotic disorder. To further investigate loci, genes and pathways associated more specifically in the well-characterized Australian Schizophrenia Research Bank cohort, we applied genome-wide single-nucleotide polymorphism analysis in these three annotation categories. METHODS: We performed a case-control genome-wide association study in 429 schizophrenia samples and 255 controls. Post-genome-wide association study analyses were then integrated with genomic annotations to explore the enrichment of variation at the gene and pathway level. We also examine candidate single-nucleotide polymorphisms with potential function within expression quantitative trait loci and investigate overall enrichment of variation within tissue-specific functional regulatory domains of the genome. RESULTS: The strongest finding (p = 2.01 × 10-6, odds ratio = 1.82, 95% confidence interval = [1.42, 2.33]) in genome-wide association study was with rs10252923 at 7q21.13, downstream of FZD1 (frizzled class receptor 1). While this did not stand alone after correction, the involvement of FZD1 was supported by gene-based analysis, which exceeded the threshold for genome-wide significance (p = 2.78 × 10-6). CONCLUSION: The identification of FZD1, as an independent association signal at the gene level, supports the hypothesis that the Wnt signalling pathway is altered in the pathogenesis of schizophrenia and may be an important target for therapeutic development.

Are familial liability for schizophrenia and obstetric complications independently associated with risk of psychotic illness, after adjusting for other environmental stressors in childhood?

OBJECTIVE: The interplay between genetic and environmental factors on risk for psychotic illness remains poorly understood. The aim of this study was to estimate independent and combined effects of familial liability for schizophrenia and exposure to obstetric complications on risk for developing psychotic illness, covarying with exposure to other environmental stressors. METHODS: This whole-population birth cohort study used record linkage across Western Australian statewide data collections (midwives, psychiatric, hospital admissions, child protection, mortality) to identify liveborn offspring (n = 1046) born 1980-1995 to mothers with schizophrenia, comparing them to offspring of mothers with no recorded psychiatric history (n = 298,370). RESULTS: Both maternal schizophrenia and pregnancy complications were each significantly associated with psychotic illness in offspring, with no interaction. Non-obstetric environmental stressors significantly associated with psychotic illness in offspring included the following: being Indigenous; having a mother who was not in a partnered relationship; episodes of disrupted parenting due to hospitalisation of mother, father or child; abuse in childhood; and living in areas of greatest socioeconomic disadvantage and with elevated rates of violent crime. Adjustment for these other environmental stressors reduced the hazard ratio for maternal schizophrenia substantially (from hazard ratio: 5.7, confidence interval: 4.5-7.2 to hazard ratio: 3.5, confidence interval: 2.8-4.4), but not the estimate for pregnancy complications (hazard ratio: 1.1, confidence interval: 1.0-1.2). The population attributable fraction for maternal schizophrenia was 1.4 and for pregnancy complications was 2.1. CONCLUSION: Our finding of a substantial decrease in risk of psychotic illness associated with familial liability for psychosis following adjustment for other environmental stressors highlights potentially modifiable risk factors on the trajectory to psychotic illness and suggests that interventions that reduce or manage exposure to these risks may be protective, despite a genetic liability.

Innovations and changes in the ICD-11 classification of mental, behavioural and neurodevelopmental disorders.

Following approval of the ICD-11 by the World Health Assembly in May 2019, World Health Organization (WHO) member states will transition from the ICD-10 to the ICD-11, with reporting of health statistics based on the new system to begin on January 1, 2022. The WHO Department of Mental Health and Substance Abuse will publish Clinical Descriptions and Diagnostic Guidelines (CDDG) for ICD-11 Mental, Behavioural and Neurodevelopmental Disorders following ICD-11's approval. The development of the ICD-11 CDDG over the past decade, based on the principles of clinical utility and global applicability, has been the most broadly international, multilingual, multidisciplinary and participative revision process ever implemented for a classification of mental disorders. Innovations in the ICD-11 include the provision of consistent and systematically characterized information, the adoption of a lifespan approach, and culture-related guidance for each disorder. Dimensional approaches have been incorporated into the classification, particularly for personality disorders and primary psychotic disorders, in ways that are consistent with current evidence, are more compatible with recovery-based approaches, eliminate artificial comorbidity, and more effectively capture changes over time. Here we describe major changes to the structure of the ICD-11 classification of mental disorders as compared to the ICD-10, and the development of two new ICD-11 chapters relevant to mental health practice. We illustrate a set of new categories that have been added to the ICD-11 and present the rationale for their inclusion. Finally, we provide a description of the important changes that have been made in each ICD-11 disorder grouping. This information is intended to be useful for both clinicians and researchers in orienting themselves to the ICD-11 and in preparing for implementation in their own professional contexts.

Rediscovering the value of families for psychiatric genetics research.

As it is likely that both common and rare genetic variation are important for complex disease risk, studies that examine the full range of the allelic frequency distribution should be utilized to dissect the genetic influences on mental illness. The rate limiting factor for inferring an association between a variant and a phenotype is inevitably the total number of copies of the minor allele captured in the studied sample. For rare variation, with minor allele frequencies of 0.5% or less, very large samples of unrelated individuals are necessary to unambiguously associate a locus with an illness. Unfortunately, such large samples are often cost prohibitive. However, by using alternative analytic strategies and studying related individuals, particularly those from large multiplex families, it is possible to reduce the required sample size while maintaining statistical power. We contend that using whole genome sequence (WGS) in extended pedigrees provides a cost-effective strategy for psychiatric gene mapping that complements common variant approaches and WGS in unrelated individuals. This was our impetus for forming the "Pedigree-Based Whole Genome Sequencing of Affective and Psychotic Disorders" consortium. In this review, we provide a rationale for the use of WGS with pedigrees in modern psychiatric genetics research. We begin with a focused review of the current literature, followed by a short history of family-based research in psychiatry. Next, we describe several advantages of pedigrees for WGS research, including power estimates, methods for studying the environment, and endophenotypes. We conclude with a brief description of our consortium and its goals.

No association between common genetic variation in FOXP2 and language impairment in schizophrenia.

The FOXP2 gene is hypothesised to be involved in schizophrenia by affecting speech and language development. Associations between common single nucleotide polymorphisms (SNPs) in FOXP2 and language have been inconsistent. We tested five previously associated SNPs for association with language in the Western Australian Family Study of Schizophrenia (n = 709, including n = 333 with schizophrenia/spectrum disorder) and found no significant associations. When we included all common FOXP2 variants, one SNP (rs2189008) was nominally associated with language. This is the most comprehensive analysis to date and indicates that common variants in FOXP2 do not play a major role in speech and language development in a clinical family sample.

Congenital blindness is protective for schizophrenia and other psychotic illness. A whole-population study.

Congenital/early blindness is reportedly protective against schizophrenia. Using a whole-population cohort of 467,945 children born in Western Australia between 1980 and 2001, we examined prevalence of schizophrenia and psychotic illness in individuals with congenital/early blindness. Overall, 1870 children developed schizophrenia (0.4%) while 9120 developed a psychotic illness (1.9%). None of the 66 children with cortical blindness developed schizophrenia or psychotic illness. Eight of the 613 children with peripheral blindness developed a psychotic illness other than schizophrenia and fewer had developed schizophrenia. Our results support findings from small case studies that congenital/early cortical but not peripheral blindness is protective against schizophrenia.

Intellectual Disability and Psychotic Disorders in Children: Association With Maternal Severe Mental Illness and Exposure to Obstetric Complications in a Whole-Population Cohort.

OBJECTIVE: Children of mothers with severe mental illness are at significantly increased risk of developing intellectual disability. Obstetric complications are also implicated in the risk for intellectual disability. Moreover, children of mothers with severe mental illness are more likely to be exposed to obstetric complications. The purpose of this study was to examine the independent and joint contributions of familial severe mental illness and obstetric complications to the risk of intellectual disability. METHOD: Record linkage across Western Australian whole-population psychiatric, inpatient, birth, and midwives' registers identified 15,351 children born between 1980 and 2001 to mothers with severe mental illness and 449,229 children born to mothers with no mental illness. Multivariable models were adjusted for paternal psychiatric status, parental intellectual disability, and other family and sociodemographic covariates. RESULTS: The risk of intellectual disability was increased among children of mothers with severe mental illness compared with children of unaffected mothers. The impact varied across maternal diagnostic groups. For children of mothers with schizophrenia, the unadjusted odds ratio was 3.8 (95% CI=3.0, 4.9) and remained significant after simultaneous adjustment for exposure to obstetric complications and other covariates (odds ratio=1.7, 95% CI=1.3, 2.3). The odds ratio for exposure to obstetric complications also remained significant after adjustment (odds ratio=1.7, 95% CI=1.6, 1.8). For intellectual disability of a genetic basis, the adjusted odds ratio for maternal schizophrenia was elevated but not statistically significant. Among children with intellectual disability, 4.2% later developed a psychotic disorder, compared with 1.1% of children without intellectual disability. CONCLUSIONS: Maternal severe mental illness and exposure to obstetric complications contribute separately to the risk of intellectual disability, suggesting potentially different causal pathways.

Use of schizophrenia and bipolar disorder polygenic risk scores to identify psychotic disorders.

BACKGROUND: There is increasing evidence for shared genetic susceptibility between schizophrenia and bipolar disorder. Although genetic variants only convey subtle increases in risk individually, their combination into a polygenic risk score constitutes a strong disease predictor.AimsTo investigate whether schizophrenia and bipolar disorder polygenic risk scores can distinguish people with broadly defined psychosis and their unaffected relatives from controls. METHOD: Using the latest Psychiatric Genomics Consortium data, we calculated schizophrenia and bipolar disorder polygenic risk scores for 1168 people with psychosis, 552 unaffected relatives and 1472 controls. RESULTS: Patients with broadly defined psychosis had dramatic increases in schizophrenia and bipolar polygenic risk scores, as did their relatives, albeit to a lesser degree. However, the accuracy of predictive models was modest. CONCLUSIONS: Although polygenic risk scores are not ready for clinical use, it is hoped that as they are refined they could help towards risk reduction advice and early interventions for psychosis.Declaration of interestR.M.M. has received honoraria for lectures from Janssen, Lundbeck, Lilly, Otsuka and Sunovian.

Cortical Brain Abnormalities in 4474 Individuals With Schizophrenia and 5098 Control Subjects via the Enhancing Neuro Imaging Genetics Through Meta Analysis (ENIGMA) Consortium.

BACKGROUND: The profile of cortical neuroanatomical abnormalities in schizophrenia is not fully understood, despite hundreds of published structural brain imaging studies. This study presents the first meta-analysis of cortical thickness and surface area abnormalities in schizophrenia conducted by the ENIGMA (Enhancing Neuro Imaging Genetics through Meta Analysis) Schizophrenia Working Group. METHODS: The study included data from 4474 individuals with schizophrenia (mean age, 32.3 years; range, 11-78 years; 66% male) and 5098 healthy volunteers (mean age, 32.8 years; range, 10-87 years; 53% male) assessed with standardized methods at 39 centers worldwide. RESULTS: Compared with healthy volunteers, individuals with schizophrenia have widespread thinner cortex (left/right hemisphere: Cohen's d = -0.530/-0.516) and smaller surface area (left/right hemisphere: Cohen's d = -0.251/-0.254), with the largest effect sizes for both in frontal and temporal lobe regions. Regional group differences in cortical thickness remained significant when statistically controlling for global cortical thickness, suggesting regional specificity. In contrast, effects for cortical surface area appear global. Case-control, negative, cortical thickness effect sizes were two to three times larger in individuals receiving antipsychotic medication relative to unmedicated individuals. Negative correlations between age and bilateral temporal pole thickness were stronger in individuals with schizophrenia than in healthy volunteers. Regional cortical thickness showed significant negative correlations with normalized medication dose, symptom severity, and duration of illness and positive correlations with age at onset. CONCLUSIONS: The findings indicate that the ENIGMA meta-analysis approach can achieve robust findings in clinical neuroscience studies; also, medication effects should be taken into account in future genetic association studies of cortical thickness in schizophrenia.

The Network Structure of Schizotypal Personality Traits.

Elucidating schizotypal traits is important if we are to understand the various manifestations of psychosis spectrum liability and to reliably identify individuals at high risk for psychosis. The present study examined the network structures of (1) 9 schizotypal personality domains and (2) 74 individual schizotypal items, and (3) explored whether networks differed across gender and culture (North America vs China). The study was conducted in a sample of 27001 participants from 12 countries and 21 sites (M age = 22.12; SD = 6.28; 37.5% males). The Schizotypal Personality Questionnaire (SPQ) was used to assess 74 self-report items aggregated in 9 domains. We used network models to estimate conditional dependence relations among variables. In the domain-level network, schizotypal traits were strongly interconnected. Predictability (explained variance of each node) ranged from 31% (odd/magical beliefs) to 55% (constricted affect), with a mean of 43.7%. In the item-level network, variables showed relations both within and across domains, although within-domain associations were generally stronger. The average predictability of SPQ items was 27.8%. The network structures of men and women were similar (r = .74), node centrality was similar across networks (r = .90), as was connectivity (195.59 and 199.70, respectively). North American and Chinese participants networks showed lower similarity in terms of structure (r = 0.44), node centrality (r = 0.56), and connectivity (180.35 and 153.97, respectively). In sum, the present article points to the value of conceptualizing schizotypal personality as a complex system of interacting cognitive, emotional, and affective characteristics.