Jim van Os

Common variants conferring risk of schizophrenia

Schizophrenia is a complex disorder, caused by both genetic and environmental factors and their interactions. Research on pathogenesis has traditionally focused on neurotransmitter systems in the brain, particularly those involving dopamine. Schizophrenia has been considered a separate disease for over a century, but in the absence of clear biological markers, diagnosis has historically been based on signs and symptoms. A fundamental message emerging from genome-wide association studies of copy number variations (CNVs) associated with the disease is that its genetic basis does not necessarily conform to classical nosological disease boundaries. Certain CNVs confer not only high relative risk of schizophrenia but also of other psychiatric disorders. The structural variations associated with schizophrenia can involve several genes and the phenotypic syndromes, or the ‘genomic disorders’, have not yet been characterized. Single nucleotide polymorphism (SNP)-based genome-wide association studies with the potential to implicate individual genes in complex diseases may reveal underlying biological pathways. Here we combined SNP data from several large genome-wide scans and followed up the most significant association signals. We found significant association with several markers spanning the major histocompatibility complex (MHC) region on chromosome 6p21.3-22.1, a marker located upstream of the neurogranin gene (NRGN) on 11q24.2 and a marker in intron four of transcription factor 4 (TCF4) on 18q21.2. Our findings implicating the MHC region are consistent with an immune component to schizophrenia risk, whereas the association with NRGN and TCF4 points to perturbation of pathways involved in brain development, memory and cognition.

Childhood Adversities Increase the Risk of Psychosis: A Meta-analysis of Patient-Control, Prospective- and Cross-sectional Cohort Studies

Evidence suggests that adverse experiences in childhood are associated with psychosis. To examine the association between childhood adversity and trauma (sexual abuse, physical abuse, emotional/psychological abuse, neglect, parental death, and bullying) and psychosis outcome, MEDLINE, EMBASE, PsychINFO, and Web of Science were searched from January 1980 through November 2011. We included prospective cohort studies, large-scale cross-sectional studies investigating the association between childhood adversity and psychotic symptoms or illness, case-control studies comparing the prevalence of adverse events between psychotic patients and controls using dichotomous or continuous measures, and case-control studies comparing the prevalence of psychotic symptoms between exposed and nonexposed subjects using dichotomous or continuous measures of adversity and psychosis. The analysis included 18 case-control studies (n = 2048 psychotic patients and 1856 nonpsychiatric controls), 10 prospective and quasi-prospective studies (n = 41 803) and 8 population-based cross-sectional studies (n = 35 546). There were significant associations between adversity and psychosis across all research designs, with an overall effect of OR = 2.78 (95% CI = 2.34–3.31). The integration of the case-control studies indicated that patients with psychosis were 2.72 times more likely to have been exposed to childhood adversity than controls (95% CI = 1.90–3.88). The association between childhood adversity and psychosis was also significant in population-based cross-sectional studies (OR = 2.99 [95% CI = 2.12–4.20]) as well as in prospective and quasi-prospective studies (OR = 2.75 [95% CI = 2.17–3.47]). The estimated population attributable risk was 33% (16%–47%). These findings indicate that childhood adversity is strongly associated with increased risk for psychosis.

The environment and schizophrenia

Psychotic syndromes can be understood as disorders of adaptation to social context. Although heritability is often emphasized, onset is associated with environmental factors such as early life adversity, growing up in an urban environment, minority group position and cannabis use, suggesting that exposure may have an impact on the developing ‘social’ brain during sensitive periods. Therefore heritability, as an index of genetic influence, may be of limited explanatory power unless viewed in the context of interaction with social effects. Longitudinal research is needed to uncover gene–environment interplay that determines how expression of vulnerability in the general population may give rise to more severe psychopathology.

The relationship between neurocognition and social cognition with functional outcomes in schizophrenia: A meta-analysis.

The current systematic review and meta-analysis provides an extended and comprehensive overview of the associations between neurocognitive and social cognitive functioning and different types of functional outcome. Literature searches were conducted in MEDLINE and PsycINFO and reference lists from identified articles to retrieve relevant studies on cross-sectional associations between neurocognition, social cognition and functional outcome in individuals with non-affective psychosis. Of 285 studies identified, 52 studies comprising 2692 subjects met all inclusion criteria. Pearson correlations between cognition and outcome, demographic data, sample sizes and potential moderator variables were extracted. Forty-eight independent meta-analyses, on associations between 12 a priori identified neurocognitive and social cognitive domains and 4 domains of functional outcome yielded a number of 25 significant mean correlations. Overall, social cognition was more strongly associated with community functioning than neurocognition, with the strongest associations being between theory of mind and functional outcomes. However, as three-quarters of variance in outcome were left unexplained, cognitive remediation approaches need to be combined with therapies targeting other factors impacting on outcome.

Strauss (1969) revisited: a psychosis continuum in the general population?

Although dichotomously defined for clinical purposes, psychosis may exist as a continuous phenotype in nature. A random sample of 7076 men and women aged 18-64years were interviewed by trained lay interviewers with the Composite International Diagnostic Interview (CIDI). Those with evidence of psychosis according to the CIDI were additionally interviewed by psychiatrists. For the 17 CIDI core psychosis items, we compared a psychiatrists rating of hallucinations and/or delusions (Clinical Psychosis; sample prevalence 4.2%) with three other possible positive CIDI ratings of the same items: (i) symptom present, but not clinically relevant (NCR Symptom; sample prevalence 12.9%); (ii) symptom present, but the result of drugs or somatic disorder (Secondary Symptom; sample prevalence 0.6%); (iii) symptom appears present, but there is a plausible explanation (Plausible Symptom; sample prevalence 4.0%). Of the 1237 individuals with any type of positive psychosis rating (sample prevalence 17.5%), only 26 (2.1%) had a DSM-III-R diagnosis of non-affective psychosis. All the different types of psychosis ratings were strongly associated with the presence of psychiatrist-rated Clinical Psychosis (NCR Symptom: OR=3.4; 95% CI: 2.9-3.9; Secondary Symptom: OR=4.5; 95% CI: 2.7-7.7; Plausible Symptom: OR=5.8; 95% CI: 4.7-7.1). Associations with lower age, single marital status, urban dwelling, lower level of education, lower quality of life, depressive symptoms and blunting of affect did not differ qualitatively as a function of type of rating of the psychotic symptom, were similar in individuals with and without any CIDI lifetime diagnosis, and closely resembled those previously reported for schizophrenia. Presence of any rating of hallucinations was strongly associated with any rating of delusions (OR=6.7; 95% CI: 5.6-8.1), regardless of presence of any CIDI lifetime diagnosis. The observation by Strauss (1969. Hallucinations and delusions as points on continua function. Arch. Gen. Psychiatry 21, 581-586) that dichotomously diagnosed psychotic symptoms in clinical samples are, in fact, part of a continuum of experiences, may also apply to the general population. The boundaries of the psychosis phenotype may extend beyond the clinical concept of schizophrenia.

Size of burden of schizophrenia and psychotic disorders

Schizophrenia is a severe mental disorder characterised by fundamental disturbances in thinking, perception and emotions. More than 100 years of research have not been able to fully resolve the puzzle that schizophrenia represents. Even if schizophrenia is not a very frequent disease, it is among the most burdensome and costly illnesses worldwide. It usually starts in young adulthood. Life expectancy is reduced by approximately 10 years, mostly as a consequence of suicide. Even if the course of the illness today is considered more favourable than it was originally described, it is still only a minority of those affected, who fully recover. The cumulative lifetime risk for men and women is similar, although it is higher for men in the age group younger than 40 years. According to the Global Burden of Disease Study, schizophrenia causes a high degree of disability, which accounts for 1.1% of the total DALYs (disability-adjusted life years) and 2.8% of YLDs (years lived with disability). In the World Health Report [The WHO World Health Report: new understanding, new hope, 2001. Geneva], schizophrenia is listed as the 8th leading cause of DALYs worldwide in the age group 15-44 years. In addition to the direct burden, there is considerable burden on the relatives who care for the sufferers. The treatment goals for the moment are to identify the illness as early as possible, treat the symptoms, provide skills to patients and their families, maintain the improvement over a period of time, prevent relapses and reintegrate the ill persons into the community so that they can lead as normal a life as possible.

A developmental model for similarities and dissimilarities between schizophrenia and bipolar disorder

Schizophrenia and mania have a number of symptoms and epidemiological characteristics in common, and both respond to dopamine blockade. Family, twin and molecular genetic studies suggest that the reason for these similarities may be that the two conditions share certain susceptibility genes. On the other hand, individuals with schizophrenia have more obvious brain structural and neuropsychological abnormalities than those with bipolar disorder; and pre-schizophrenic children are characterised by cognitive and neuromotor impairments, which are not shared by children who later develop bipolar disorder. Furthermore, the risk-increasing effect of obstetric complications has been demonstrated for schizophrenia but not for bipolar disorder. Perinatal complications such as hypoxia are known to result in smaller volume of the amygdala and hippocampus, which have been frequently reported to be reduced in schizophrenia; familial predisposition to schizophrenia is also associated with decreased volume of these structures. We suggest a model to explain the similarities and differences between the disorders and propose that, on a background of shared genetic predisposition to psychosis, schizophrenia, but not bipolar disorder, is subject to additional genes or early insults, which impair neurodevelopment, especially of the medial temporal lobe.

The incidence and outcome of subclinical psychotic experiences in the general population.

OBJECTIVES To examine the incidence and 2-year stability and outcome of subclinical psychotic experiences in the general population. DESIGN The Netherlands Mental Health Survey and Incidence Study (NEMESIS), a longitudinal general population study. METHODS A representative population sample of 7,076 participants was interviewed with the composite international diagnostic interview at baseline, 1 year later at T(1) and again 2 years later at T(2). A sample of individuals was identified who had onset of a new, broadly defined psychotic experience between baseline and T(1) (N = 79; incidence = 2%). Stability and outcome of these incident positive psychotic experiences was reassessed by interview at T(2), at which 25 individuals had a CIDI rating of broadly defined psychotic experience (subclinical outcome) and 11 individuals had psychotic experiences with functional impairment and need for care (clinical outcome). RESULTS The majority of individuals with an incident psychotic experience did not display persistence of the experience. Only 8% of individuals with a T1 incident psychotic experience had evidence of a T2 subclinical outcome, and only 8% had evidence of a T2 clinical outcome. The emotional context and the number of the T1 incident psychotic experiences were strong modifiers of predictive power for the clinical outcome, but not (or to a much lesser extent) for the subclinical outcome. CONCLUSIONS The incidence of positive psychotic experiences in the general population is around 100 times greater than traditional estimates of incidence of psychotic disorder such as schizophrenia. The far most likely outcome for these experiences is discontinuity. For the small proportion who display continuity, there is an equally large likelihood of subclinical and clinical 2-year outcomes. Emotional appraisal and degree of intrusiveness of psychotic experiences are important modifiers not for continuity per se but for clinical outcome specifically.

Children's health-related quality of life, neighbourhood socio-economic deprivation and social capital. A contextual analysis

Neighbourhood objective socio-economic indicators and community-reported subjective measures of social capital were examined in relation to childrens health-related quality of life in the Netherlands. Three different data-sources were used: (1) objective neighbourhood socio-economic indicators, (2) subjective neighbourhood data on social capital, and (3) individual data of a family cohort study, including questions on childrens health-related quality of life, and family socio-economic status. Multilevel analyses were conducted using both neighbourhood level and individual level data. Neighbourhood socio-economic status and social capital were associated. Measures of socio-economic deprivation and social capital were both non-specifically associated with childrens general health and satisfaction, independent of possible individual-level confounders. However, childrens mental health and behaviour were specifically associated with one aspect of social capital, the degree of informal social control in the neighbourhood.

Alterations in theory of mind in patients with schizophrenia and non-psychotic relatives

Objective: It has been proposed that alterations in theory of mind underlie specific symptoms of psychosis. The present study examined whether alterations in theory of mind reflect a trait that can be detected in non‐psychotic relatives of patients with schizophrenia.