No abstract

The epidemiology of first-episode psychosis is poorly understood because of the paucity of systematic studies, yet it constitutes the fundamental basis for understanding the disorder and the foundations on which clinical, biological, therapeutic, and long-term outcome studies are built. A particular need is to clarify the diagnostic breadth of first-episode psychosis and, on this basis, to undertake systematic comparisons across representative populations of the psychoses, to include comparisons with first-episode mania. Considered here is the new generation of prospective studies that may be able to inform in some way on these issues. Attainment of the above goals requires prolonged accrual of "all" cases of nonaffective, affective, and any other psychotic illness, including first-episode mania, to derive the required representative populations. To illustrate some of the challenges, the structure of the Cavan-Monaghan prospective first episode study is described and its interim findings are outlined, as rural Ireland provides psychiatric care based on strict catchment areas and is characterized by substantive ethnic and socioeconomic homogeneity and stability. It is argued that there are 3 primary diagnostic nodes (schizophrenia spectrum psychosis, bipolar disorder, and major depressive disorder with psychotic features) around which there exist numerous additional, overlapping, and well-populated diagnostic categories that are distinct only in terms of their operational definition. Only through systematic, epidemiologically based studies that access this intrinsic diversity are we likely to understand fully the origins and pathobiology of first-episode psychosis.

A recent study identified a putative association between variants in the regulator of G-protein signalling 4 (RGS4) and schizophrenia, Chowdari et al. [2002: Hum Mol Genet 11: 1373-1380]. RGS4 is both a positional and functional candidate gene for schizophrenia. Chowdari and colleagues identified association at this locus in a number of distinct and ethnically diverse samples, although the pattern of association was not the same in all the samples. Our study attempted to replicate this association in an independent Irish sample of schizophrenia cases and controls. We succeeded in detecting evidence of association at the RGS4 locus. The signal comes from a four-marker haplotype that is in significant excess in our case sample. The same haplotype is in excess in the Caucasian schizophrenia sample used by Chowdari et al. [2002: Hum Mol Genet 11: 1373-1380]. This study provides further support for the contribution of RGS4 to schizophrenia susceptibility.

Two recent association studies have implicated the neuregulin-1 gene (NRG1) at chromosome 8p21-22 as a susceptibility gene for schizophrenia. Stefansson et al identified three 'at-risk' haplotypes (HapA, B and C) which spanned the NRG1 locus and shared a common core haplotype. Subsequently, they demonstrated evidence that the core haplotype was associated with schizophrenia in an independent Scottish sample. To confirm and refine this haplotype we investigated the NRG1 locus in an independent Irish case-control sample. We did not find the core haplotype to be associated in our sample. However, we identified a refined 2-marker haplotype (HapB(IRE)) that shared common alleles with one of the Icelandic 'at-risk' haplotypes and is in significant excess in the Irish cases (19.4%) vs controls (12.3%) (P=0.013). This refined 'at-risk' haplotype is also in significant excess in the Scottish case sample (17.0% vs 13.5%; P=0.036). Interestingly, this refined 'at-risk' haplotype is positioned close to an EST cluster of unknown function (Hs.97362) within intron 1 of NRG1.