There is an urgent need for strategic research designed to generate and rigorously test candidate nongenetic, risk-modifying factors for schizophrenia. A framework for the primary prevention of schizophrenia can be built on this type of research.

While we have some broad clues in the form of risk indicators (urban birth, season of birth, pregnancy and birth complications), we need to ‘fine map’ these domains.

We should continue to try to identify novel domains from which to generate candidate exposures. One way to look for clues is to identify disease gradients and then search for clues to explain these gradients.  These gradients can be across time (season of birth, between-year variability) and across space (neighbourhood variation, urban - rural gradient and latitude gradients in prevalence). Within medical epidemiology, migrant studies have played an important role in generating candidate exposures. They can vary the environmental factors while ‘holding’ ethnicity constant (and,  it is assumed,  a degree of genetic variability)  (Hennekens and Buring, 1987). The cause of the increased risk of psychosis in second-generation African - Caribbeans born in the UK is still unclear. These studies of schizophrenia in migrant groups may help to generate awareness of novel candidate exposures (Harrison et al., 1997; McDonald and Murray, 2000).

It is essential that the data used to address this problem are derived from epidemiologically informed sampling frames. Sample sizes need to be representative of the underlying population so the PAR values that guide public health planning can be generated. Links between candidate exposures and genetic epidemiology will also be crucial for future research.

Just as candidate genes are ranked according to various rules (e.g.  are they located in a ‘hot spot’, how many introns/exons within the gene, biological plausibility, etc.?), those interested in exposures need sorting rules. When rank-ordering candidate exposures for more intense scrutiny, there is a case to prioritise those with universal public health potential (e.g. vaccinations for infectious agents, nutritional supplements). If the exposure is already associated with disorders other than schizophrenia, then this makes it a more attractive candidate from a public health perspective (single interventions could lead to improvements in multiple outcomes).

Epidemiological research can serve to ‘sharpen the focus’, allowing candidate risk factors to be identified. However, history has shown that risk factor epidemiology can sometimes enter cycles of uninformative replications (‘circular epidemiology’: Kuller, 1999). Season of birth has been studied as a risk factor for 80 years with little real progress in identifying the underlying risk-modifying exposure. In reaction to this, some research groups are looking to developments in the neurosciences in order to test the impact of candidate exposures on neuronal development, both in vitro and in whole animal studies. Such analyses range from gene expression profiling through to cognitive psychology techniques such as prepulse inhibition.

These techniques are removed from the schizophrenia phenotype, but nevertheless can provide valuable evidence about the biological plausibility of candidate risk factors. Dialogue between those involved in risk factor epidemiology and those in developmental neurobiology can provide new clues about the potential timing of exposures (e.g.  vulnerable periods of brain development)  and broad classes of exposure (e.g. exposures that may impact on neural apoptosis, migration, etc.).

Such scientific cross-fertilization can be informative for basic neuroscience as well.

Clues from epidemiology linked vitamin A and increased risk of craniofacial abnormality, which then led to the discovery of the role of retinoic acid in brain development and ultimately to its nomination as a potential risk factor for schizophrenia (LaMantia, 1999).

Animal models for schizophrenia based on developmental interventions include lesions in selected brain areas (Lipska et al., 1993) prenatal exposure to specific viruses such as influenza (Fatemi et al., 1999) and Borna virus (Hornig et al., 1999), and prenatal hypoxic/ischaemic insults (Mallard et al.,  1999).  The potential to extend this type of research with the use of genetic knock-out mice (to test gene - environment interactions) and gene expression profiling (cross-referencing altered gene expression in animal experiments with gene expression studies in schizophrenia) offers powerful new tools to the neuroscience community. This type of research may galvanize the search for novel nongenetic risk factors for schizophrenia.

Sartorius and Henderson (1992) proposed three options for the research community interested in the primary prevention of mental illness. The first option was to forget about primary prevention completely and concentrate on better treatments and cures. The second option was to fund more research in order to discover the causes of serious psychiatric illness and then commence primary prevention.

The final option was to start primary prevention based on existing knowledge, albeit imperfect. Clearly, we need a balance of all three approaches. Basic strategic research needs to go hand in hand with attempts at primary prevention. The nihilism and despair of the past needs to be replaced by a sense of determination and urgency. The dream of making the primary prevention of schizophrenia a reality may be quixotic, but it is certainly not impossible.

Acknowledgement

The project described in this section was supported by the Stanley Foundation.

John McGrath
Queensland Centre for Schizophrenia Research, Wolston Park Hospital, Wacol, Australia

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