Press conference on the occasion of the 23rd ECNP Congress, Aug. 29, 2010, Amsterdam
The incidence of psychotic disorders varies greatly across places and demographic groups, as do symptoms, course, and treatment response across individuals. High rates of schizophrenia in large cities, and among immigrants, cannabis users, and traumatised individuals reflect the causal influence of environmental exposures. This, in combination with progress in the area of molecular genetics, has generated interest in more complicated models of schizophrenia aetiology that explicitly posit gene-environment interactions.
Unravelling the causes of psychotic disorders
Schizophrenia and related psychotic disorders have a complex aetiology. Research has attempted to determine the role of specific biological variables, such as genetic and biochemical factors and subtle changes in brain morphology. Genetic vulnerability in schizophrenia is shared in part with bipolar disorder and recent molecular genetic findings also indicate an overlap with developmental disorders such as autism (Van Os & Kapur, 2009). According to twin and family studies more than half of the vulnerability for schizophrenia is of genetic origin. However, attempts to discover genes that relate directly to psychotic disorder have been frustrating and often disappointing, and despite enormous investments, the identification of actual molecular genetic variants underlying schizophrenia liability has proven extremely difficult. This difficulty is mainly due to the phenomenon of gene-environment interaction, which is defined as genetic control of sensitivity to the environment.
Exciting findings in other areas of psychiatry have motivated researchers to turn their attention to better understanding the complex ways in which genetic factors interact with non-genetic factors to produce psychosis. Biological vulnerability factors with a genetic background interact with complex physical, psychological and environmental vulnerability factors. Conceptualised in a model, gene-environment interaction proposes that genes influencing risk for schizophrenia may not do so directly (the dominant model until recently), but indirectly by making individuals more sensitive to the effects of causal environmental risk factors.
The 'genotype x environmental interaction' approach differs from the linear gene-phenotype approach by positing a causal role not for either genes or environment in isolation but for their synergistic co-participation in the cause of psychosis where the effect of one is conditional on the other (Van Os et al., 2008). Gene-environment interaction seems a particularly suitable approach for understanding the development of psychosis because this phenotype is known to be associated with environmentally mediated risks, yet people display considerable heterogeneity in their response to those environmental exposures.
In the framework of gene-environment interaction, research is focussing on subclinical symptoms that can be traced to prior persistence of clinically relevant symptoms. For example, in a substantial proportion of patients with bipolar disorder, onset of illness may be seen as the poor outcome of a developmentally common and usually transitory non-clinical bipolar phenotype (Tijssen et al., 2010).
In schizophrenia and related psychotic disorders, the median prevalence of subclinical psychotic experiences is reported to be around 5% and the median incidence rate to be around 3%. The difference between prevalence and incidence rates, together with data from follow-up studies, indicates that approximately 75% of developmental psychotic experiences are transitory and disappear over time. There is evidence, however, that transitory developmental expression of psychosis ('psychosis proneness') may become abnormally persistent ('persistence') and subsequently clinically relevant ('impairment'), depending on the degree of environmental risk the person is additionally exposed to (Van Os et al., 2009; Dominguez et al., 2009). According to the model of psychosis proneness - persistence - impairment, genetic background factors impact on a broadly distributed and transitory population expression of psychosis during development. Hence, poor prognosis, in terms of persistence and clinical need, can be predicted by environmental exposure interacting with genetic risk.
Environmental risk factors
According to findings from epidemiological research, rates of schizophrenia and related psychotic disorders are substantially influenced by a spectrum of environmental risk factors with significant impact on children and adolescents growing up in European societies.
- Urbanicity
Growing up in an urban area has been shown to be associated with an increased risk of developing psychotic disorder in later life (Spauwen et al., 2004). For children growing up in big cities a more than twofold risk compared to children in rural environments has been shown, independent of other risk factors. According to latest research findings up to 25% of all schizophrenia cases can be attributed to this effect. - Migration
Migration presents an increasing challenge to European countries. In immigrant populations the risk of developing psychotic disorders is much higher compared to the risk in both the host country and the country of origin. These findings point to a significant impact associated with the often problematic social interaction between migrants and majority populations. - Cannabis use
Apart from alcohol, cannabis is the most widely used drug in Europe. Although its effects were considered to be harmless compared to other drugs until recently, many studies have shown that cannabis use, in particular heavy use during adolescence, increases the risk of psychotic disorders such as schizophrenia. - Childhood victimisation
In European countries at least 15% of populations are the victims of significant abuse, neglect or bullying during childhood. Evidence from epidemiological research pointing to a link between childhood trauma and psychotic disorders is remarkably consistent in showing strong effects on disease vulnerability.
Measuring schizophrenia vulnerability caused by gene-environment interaction
Given substantial gene-environment interaction underlying schizophrenia and related psychotic disorders, the most promising approach to elucidate the causes of schizophrenia is to focus on both genes and environments in the same research project. The study of gene-environment interaction is a multidisciplinary exercise involving epidemiology, psychology, psychiatry, neuroscience, neuro-imaging, pharmacology, biostatistics, and genetics. However, it has proven extremely difficult to bring together these disciplines. Now for the first time in the European Union a rational strategy of focused research collaboration has been devised with a unique, large-scale project, which aims to unravel the causes of schizophrenia and related psychotic disorders (EU-GEI project, see below).
The EU-GEI project