CLINICAL HANDBOOK OF SCHIZOPHRENIA

7. Environmental Pre- and Perinatal Influences in Etiology 71in offspring. Specifically, interleukin-8 (IL-8) during second and third trimesters andTNF-alpha at the time of birth (both proinflammatory cytokines) have been linked to increasedincidence of psychosis in offspring.In addition to the direct neurotoxic effects of fetal exposure to proinflammatorycytokines, emerging evidence suggests that genetic polymorphisms found in schizophreniapopulations may make certain individuals more susceptible to the negative effects ofinfection and inflammation. TNF-a (promoter region A2) and IL-1 complex [IL-1-alpha(-889) allele 2, IL-1-beta (-511) allele 1, and IL-1RA allele 1] genetic polymorphisms havebeen associated with schizophrenia outcome. These polymorphisms typically lead to bothproduction of proinflammatory cytokines without any known infection (i.e., basal levels)and overproduction of proinflammatory cytokines in response to infection. Although individualswith these polymorphisms do not always develop schizophrenia, they appear tobe more vulnerable to multiple diseases and infections. Therefore, it is possible that carriersof genetic polymorphisms associated with inflammation could be more vulnerable tothe damaging effects of prenatal infection, thus increasing the likelihood of psychotic onsetin adulthood; however, no studies have directly tested this gene–environment interaction.Cumulatively, studies implicate a series of prenatal infections in the etiology ofschizophrenia. Nevertheless, it appears as though the deleterious effects of exposure toprenatal infection may be more related to maternal immune responses to infection thanto the direct effects of the pathogen, given that most pathogens do not cross the placenta.Specifically, prenatal exposure to maternal proinflammatory cytokines has been found toalter multiple areas of the brain that have been implicated in schizophrenia, and thesecytokines have been linked to psychotic outcome in offspring. In addition, geneticpolymorphisms associated with overproduction of proinflammatory cytokines have beenfound in patients with schizophrenia, suggesting that individuals who later developschizophrenia may be particularly vulnerable to infection and other prenatal insults. Last,both infection and proinflammatory cytokines have been linked to increased fetalhypoxia, which has been associated with schizophrenia and many of the brain abnormalitieslinked to the disorder. The availability of studies using serological data and the possibilityof examining direct gene–environment interactions likely will lead to a much betterunderstanding of the molecular pathways linking OCs to schizophrenia outcome, whichis the starting point for developing treatment and early intervention strategies.THE NEURODEVELOPMENTAL MODEL OF SCHIZOPHRENIAThe neurodevelopmental model of schizophrenia provides a framework for understandinghow OCs interact with the developing brain to increase the likelihood of schizophreniain late adolescence and early adulthood. In normal development, connections in thebrain (referred to as synaptic density) increase until an individual is approximately 2years of age, which slowly decline during childhood, then decline steeply during latechildhood and early adolescence. Many of these connections are unnecessary and will beeliminated in the mature brain. During adolescence, a sharp increase in a process calledsynaptic pruning, which involves the elimination of superfluous connections, coincideswith the emergence of abilities to solve abstract and complex problems. According to theneurodevelopmental model, patients with schizophrenia may have too many, too few, orunnecessary synaptic connections that are eliminated during adolescence, which results inthe onset of psychotic symptomatology. According to one model, schizophrenia would