The role of genes, stress, and dopamine in the development of schizophrenia

The dopamine hypothesis is the longest standing pathoetiologic theory of schizophrenia. Because it was initially based on indirect evidence and findings in patients with established schizophrenia, it was unclear what role dopamine played in the onset of the disorder. However, recent studies in people at risk of schizophrenia have found elevated striatal dopamine synthesis capacity and increased dopamine release to stress. Furthermore, striatal dopamine changes have been linked to altered cortical function during cognitive tasks, in line with preclinical evidence that a circuit involving cortical projections to the striatum and midbrain may underlie the striatal dopamine changes. Other studies have shown that a number of environmental risk factors for schizophrenia, such as social isolation and childhood trauma, also affect presynaptic dopaminergic function. Advances in preclinical work and genetics have begun to unravel the molecular architecture linking dopamine, psychosis, and psychosocial stress. Included among the many genes associated with risk of schizophrenia are the gene encoding the dopamine D2 receptor and those involved in the upstream regulation of dopaminergic synthesis, through glutamatergic and gamma-aminobutyric acidergic pathways. A number of these pathways are also linked to the stress response. We review these new lines of evidence and present a model of how genes and environmental factors may sensitize the dopamine system so that it is vulnerable to acute stress, leading to progressive dysregulation and the onset of psychosis. Finally, we consider the implications for rational drug development, in particular regionally selective dopaminergic modulation, and the potential of genetic factors to stratify patients

The effect of increasingly stringent diagnostic criteria on sex differences in schizophrenia

Sex differences in premorbid function and symptomatology were examined as increasingly stringent criteria for schizophrenia were applied to 182 male and 139 female . psychotic patients. The male/female ratio rose from 1.6 among those meeting the CATEGO 'broad' criteria for schizophrenia to 3.7 among those satisfying DSM-III criteria. Of 76 women meeting the former criteria, 53 were excluded by the latter, the majority rediagnosed as affective or schizo-affective psychosis. Consequently, although women meeting CATEGO 'broad' criteria showed more affective and fewer typical schizophrenic symptoms than their male counterparts, these differences were abolished by DSM-III criteria. Among CATEGO 'broad' schizophrenics, men were more likely than women to have received special education, and had shown worse childhood social adjustment and worse adult social achievement than women. These differences disappeared among DSM-III schizophrenics, but women continued to have fewer premorbid schizoid and schizotypal traits, a greater likelihood of marriage, and a later age of onset

A population-level prediction tool for the incidence of first-episode psychosis: translational epidemiology based on cross-sectional data

Objectives: Specialist early intervention services (EIS) for people aged 14–35 years with first episodes of psychosis (FEP) have been commissioned throughout England since 2001. A single estimate of population need was used everywhere, but true incidence varies enormously according to sociodemographic factors. We sought to develop a realistically complex, population-based prediction tool for FEP, based on precise estimates of epidemiological risk. Design and participants: Data from 1037 participants in two cross-sectional population-based FEP studies were fitted to several negative binomial regression models to estimate risk coefficients across combinations of different sociodemographic and socioenvironmental factors. We applied these coefficients to the population at-risk of a third, socioeconomically different region to predict expected caseload over 2.5 years, where the observed rates of ICD-10 F10-39 FEP had been concurrently ascertained via EIS. Setting: Empirical population-based epidemiological data from London, Nottingham and Bristol predicted counts in the population at-risk in the East Anglia region of England. Main outcome measures: Observed counts were compared with predicted counts (with 95% prediction intervals (PI)) at EIS and local authority district (LAD) levels in East Anglia to establish the predictive validity of each model. Results: A model with age, sex, ethnicity and population density performed most strongly, predicting 508 FEP participants in EIS in East Anglia (95% PI 459, 559), compared with 522 observed participants. This model predicted correctly in 5/6 EIS and 19/21 LADs. All models performed better than the current gold standard for EIS commissioning in England (716 cases; 95% PI 664–769). Conclusions: We have developed a prediction tool for the incidence of psychotic disorders in England and Wales, made freely available online (http://www.psymaptic.org), to provide healthcare commissioners with accurate forecasts of FEP based on robust epidemiology and anticipated local population need. The initial assessment of some people who do not require subsequent EIS care means additional service resources, not addressed here, will be required