Schizophrenia Bulletin

Schizophrenia Bulletin Advance Access originally published online on September 8, 2005
Schizophrenia Bulletin 2005 31(4):795-799; doi:10.1093/schbul/sbi060

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Schizophrenia and Urbanicity: A Major Environmental Influence—Conditional on Genetic Risk

Lydia Krabbendam
Department of Psychiatry and Neuropsychology, South Limburg Mental Health Research and Teaching Network, EURON, Maastricht University, Maastricht, the Netherlands

Jim van Os
Department of Psychiatry and Neuropsychology, South Limburg Mental Health Research and Teaching Network, EURON, Maastricht University, Maastricht, the Netherlands
Division of Psychological Medicine, Institute of Psychiatry, De Crespigny Park, London

	Abstract

Top Abstract Introduction The Urban-Rural Contrast Is the Association True? Clues to the Nature... Is the Effect Conditional... Identifying the Exposure: Focus... References

 
More than 10 studies have consistently shown that around one-third of all schizophrenia incidence may be related to unknown but likely unconfounded environmental factors operating in the urban environment that have an impact on developing children and adolescents to increase, relatively specifically, the later expression of psychosis-like at-risk mental states and overt psychotic disorders. The available evidence suggests that causation (urban environment causes psychosis) is more important than selection (high-risk individuals move into urban areas) and that the effect of the environmental factors in the urban environment is conditional on genetic risk (i.e., there may be gene–environment interaction). The effect associated with urbanicity has grown in more recent birth cohorts, while studies focusing on within-city contrasts have found important within-city variation in the incidence of schizophrenia associated with neighborhood social characteristics. Future approaches may focus on the complex interactions between neighborhood cognitive social capital and genetic risk as the substrate for the increased incidence of schizophrenia in the increasingly urbanized areas that children are growing up in.

Keywords: schizophrenia / environment / urban areas / genetics

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	Introduction

Top Abstract Introduction The Urban-Rural Contrast Is the Association True? Clues to the Nature... Is the Effect Conditional... Identifying the Exposure: Focus... References

 
Ever since the early seminal studies of Farris and Dunham in the United States¹ and Hare in the United Kingdom,^2–3 showing that the rate of schizophrenia was higher in the centers of urbanized areas, the city has been the subject of increasingly sophisticated research into the geographical variation of schizophrenia, in terms of both urban–rural comparisons and within-city, neighborhood-associated variation. The importance of this type of research lies in the fact that urban–rural contrasts and within-city neighborhood contrasts in the rate of a disorder can point to the impact of environmental factors and, in the case of multifactorial disorders such as schizophrenia, associated gene–environment interactions.⁴ As it is increasingly likely that genetic effects in schizophrenia are to a large degree conditional on the environment and vice versa, that environmental effects are conditional on genetic risk,⁵ the elucidation of the environmental influences that currently go under the name of "urbanicity" is a crucial step in unraveling the etiology of schizophrenia.

	The Urban–Rural Contrast

Top Abstract Introduction The Urban-Rural Contrast Is the Association True? Clues to the Nature... Is the Effect Conditional... Identifying the Exposure: Focus... References

 
The effect sizes from 10 studies examining the rate of schizophrenia in urban as compared to rural areas are meta-analyzed in table 1, ^6–15 using STATA statistical software to conduct a random effects meta-analysis. Two studies (finding positive associations) were not included, as no effect size on the multiplicative scale could be extracted.^16–17 For each study with more than 2 levels of urbanicity, the contrast between the reference category and the highest value of urbanicity was used. Some studies defined urbanicity as the number of people relative to area surface; others, as number of addresses relative to area surface; and yet others, as large city versus small city based on absolute population counts. Some examined urban residence, and most examined urban birth or urban upbringing, although the importance of this distinction is limited, given the fact that urban birth and urban residence are strongly associated.¹⁸ The meta-analysis of these studies indicates that the rate of schizophrenia in (variably defined) urban areas is around double the rate of that in (variably defined) rural areas. The studies address a range of possible confounders such as age, sex, ethnicity, drug use, social class, family history, season of birth, and many others, none of which could explain the apparent association between urbanicity and psychotic disorders. Also, results were apparent both for studies that depended on hospital admission in defining schizophrenia and for studies that defined the outcome regardless of any contact with services. Therefore, the oldest proposed explanation for the urban–rural difference—reduced distance to a psychiatric hospital in urban areas¹⁹—can also be discarded.

View this table: [in this window] [in a new window]   Table 1. Studies Examining Associations Between Urbanicity and Psychosis Outcomes

 

	Is the Association True?

Top Abstract Introduction The Urban-Rural Contrast Is the Association True? Clues to the Nature... Is the Effect Conditional... Identifying the Exposure: Focus... References

 
Although confounding factors and differential use of mental health services are unlikely explanations for the high rates of psychotic disorder in urban areas, an important alternative explanation is that it is not urbanicity that causes higher rates of schizophrenia (causation hypothesis) but, rather, that more individuals with genetic liability for schizophrenia move into urban areas (selection hypothesis). This explanation, however, is unlikely to account for a major part of the association because of several reasons. First, several studies have adjusted for indicators of genetic risk and found only slightly reduced associations (e.g., ^{9, 20}). Second, and most important, if genetic risk was the true exposure explaining the associations between the apparent exposure of urbanicity and schizophrenia, then changes in the apparent exposure of urbanicity during childhood should not modify later risk of schizophrenia, because the true exposure of genetic risk would remain unchanged. This, however, is not the case, as 2 studies show that early changes in urbanicity exposure are associated with corresponding changes in schizophrenia risk later in adulthood.^{18, 21} It can therefore be concluded that intra- or intergenerational drift or other forms of spatial selective mobility are unlikely to be the main factor explaining the high rates of psychosis in urban areas.²² These results, together with the fact that (i) the findings are remarkably consistent across countries and cultures even though the effect size is modest,¹⁵ (ii) dose–response relationships between urbanicity and schizophrenia have been demonstrated in many studies, and (iii) urban birth and upbringing precede schizophrenia onset rather than the other way around, suggest that the association between urbanicity and schizophrenia not only is likely true but also may be causal. However, a crucial element necessary for making the step from association to cause is lacking: that of a plausible mechanism detailing the pathway from impact of the exposure to onset of psychotic symptoms. Urbanicity is merely a proxy description for some underlying environmental factor or factors in urban areas, and these need to be identified first before further progress can be made.

	Clues to the Nature of Urbanicity Exposure

Top Abstract Introduction The Urban-Rural Contrast Is the Association True? Clues to the Nature... Is the Effect Conditional... Identifying the Exposure: Focus... References

 
Although it may not be clear yet what exactly constitutes the urban exposure, several clues to its nature are apparent. First, there is general agreement that the kind of geographical variation in incidence associated with urbanization is indicative of an environmental effect and that this effect has its impact through continuous or repeated exposure.^21–22 Second, the exposure exerts its influence during development in childhood and adolescence, not in adulthood around the time of onset of illness.^{18, 21} Third, the proxy environmental risk factor of growing up in an urban environment (and any other risk it interacts with) explains around 30% of all schizophrenia incidence, assuming causality,^{12, 23} making it potentially the most important of all environmental risk factors proposed for schizophrenia. Fourth, recent studies have shown that the increased level of risk for psychotic disorder in urban populations is not phenotypically silent, because the rate of at-risk mental states characterized by subtle psychosis-like phenomena, with prevalences of 10–20%, is also higher in urban areas, independent of the increased rate of psychotic disorder and independent of service use, sociodemographic factors including ethnic group, drug use, and size of social network (e.g., ^{6, 13, 17, 24}). Fifth, recent analyses also suggest that the increased risk for clinical and nonclinical expressions of psychosis in urban areas is not mediated by neuropsychological impairment, traffic air pollution, childhood social position, or obstetric complications.^{7, 17, 22, 25} Sixth, several studies have demonstrated that (i) the association between urban environment and schizophrenia is higher in the more recent birth cohorts, indicating that the impact of urbanicity increases with time; and (ii) the impact of the urban environment is greater in younger persons as compared to older persons.^{12, 16} Seventh, although the incidence of other disorders may also be higher in urban areas, the effect size for schizophrenia appears to be much larger.^{10, 26}

The combined information from these clues indicates that prevalent factors in the urban environment have an impact during development to raise the broad expression of psychosis in the population, the extreme of which will be detectable as a higher incidence of psychotic disorders. The fact that the effect associated with urbanicity is rising with time makes it unlikely that infectious factors play a role, as the effect of these has greatly decreased over the periods examined in the various studies. The fact that any impact of the urban environment is not associated with neuropsychological impairment or obstetric complications makes exposures causing neurodevelopmental alterations less likely. Similarly, the fact that size of social network and childhood social position did not mediate the impact of the urban environment makes social isolation as an underlying cause less likely. Finally, a generic effect of stress is unlikely given the specificity of the association with schizophrenia rather than, for example, bipolar disorder.

	Is the Effect Conditional on Genetic Risk?

Top Abstract Introduction The Urban-Rural Contrast Is the Association True? Clues to the Nature... Is the Effect Conditional... Identifying the Exposure: Focus... References

 
A final and important clue as to the mechanism whereby factors in the urban environment raise the rate of schizophrenia comes from recent work suggesting a general mechanism of gene–environment interaction. As many people live in urban areas but only a tiny minority of these will develop schizophrenia, it is likely that the urban exposure is conditional on some other factor. Three recent studies using indirect measures of genetic risk have suggested that there is synergism between environmental factors in the urban environment, on the one hand, and familial morbid risk^{20, 27} and psychometric expression of psychosis liability,²⁸ on the other. The data presented in these studies suggest that most of the impact of the environmental factors in the urban environment is conditional on preexisting indicators of genetic risk for psychosis.

	Identifying the Exposure: Focus on Within-City Contrasts

Top Abstract Introduction The Urban-Rural Contrast Is the Association True? Clues to the Nature... Is the Effect Conditional... Identifying the Exposure: Focus... References

 
Current approaches in the study of the urban environment in relation to schizophrenia have possibly reached their limit of usefulness. The work conducted so far has considered the urban environment and the large city as homogeneous entities, but in actual fact there are important within-city contrasts, the study of which may aid in identifying the factors in the urban environment that act to specifically increase the risk for schizophrenia. The incidence of schizophrenia, contrary to that of common mental disorders,²⁹ is not the same across small areas such as neighborhoods,^{1–3, 30–31} and recent work using statistical techniques to separate neighborhood from individual effects has confirmed nonrandom variation across neighborhoods and the fact that this variation is associated not with indicators of material deprivation but, rather, with indicators of social isolation.^{1, 3, 32} Given the fact that social isolation by itself does not appear to mediate the effect of urbanicity as discussed above, some other, related measure may be invoked. Recent studies have focused on the developmental effects of variables referred to as "social capital" or the "glue that holds society together."^{33(pp 280)} These studies have suggested that in particular cognitive social capital, or aspects of the degree of mutual trust, bonding, and safety in neighborhoods, exerts a developmental impact on the mental health of the children growing up in these environments.^34–36 The hypothesized effects of cognitive social capital can be readily integrated with current hypotheses of cognitive neuropsychiatric models of psychotic symptoms,³⁷ in combination with hypotheses about genes involved in gene–environment interactions in psychosis (e.g., ³⁸). This and other future approaches may help in identifying the mechanisms that drive up to a third of schizophrenia incidence.

	Footnotes

 
To whom correspondence should be addressed; tel: 31-43-3882582, fax: 31-43-3882578, e-mail: l.krabbendam{at}sp.unimaas.nl

	References

Top Abstract Introduction The Urban-Rural Contrast Is the Association True? Clues to the Nature... Is the Effect Conditional... Identifying the Exposure: Focus... References

 

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