Article

The relationship of schizophrenic births to 16 infectious diseases

University College London, Londinium, England, United Kingdom
The British Journal of Psychiatry (Impact Factor: 7.34). 10/1994; 165(3):353-6. DOI: 10.1192/bjp.165.3.353
Source: PubMed

ABSTRACT Recently, several investigators have reported an association between influenza epidemics and increased birth rates of 'preschizophrenic' individuals some four to six months later. Here we examine whether maternal exposure to other infectious diseases can also predispose the foetus to later schizophrenia.
Two independent sets of dates of birth of first admission schizophrenic patients, born between 1938 and 1965 in England and Wales, were obtained from the Mental Health Enquiry in England and Wales. Data on the number of deaths per month from 16 infectious diseases between 1937 and 1965 in England and Wales were also collected. We used a Poisson regression model to examine the relationship between deaths from infectious diseases and schizophrenic births.
In the two separate data sets, increased national deaths from bronchopneumonia preceded, by three and five months respectively, increased numbers of schizophrenic births. We did not find any other significant associations between schizophrenic births and any of the other 15 infectious diseases.
The association between deaths from bronchopneumonia and increased schizophrenic births some months later may be a reflection of the fact that bronchopneumonia deaths increase markedly during influenza epidemics.

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    • "To attain these goals, we have used the " prenatal poly I:C model " which is one of the models within a larger class of neurodevelopmental models based on gestational maternal infection or immune stimulation (for reviews see Boksa, 2010; Meyer and Feldon, 2010; Meyer et al., 2009, 2005; Patterson, 2009). Prenatal exposure to infection has been implicated by both retrospective and recently prospective epidemiological studies as a risk factor for SCZ (Adams et al., 1993; Brown et al., 2004a,b, 2009; Brown and Derkits, 2010; Brown and Susser, 2002; Izumoto et al., 1999; Mednick et al., 1994; O'Callaghan et al., 1994; Torrey et al., 1988). Although the mechanism/s whereby viral infection during neural development can cause brain pathology remain to be clarified, there is increasing evidence that the maternal immune response, and in particular pro-inflammatory cytokines released by the maternal immune system, is a factor interfering with fetal brain development (Gilmore and Jarskog, 1997; Gilmore et al., 2003, 2005; Hornig and Lipkin, 2001; Marx et al., 2001; Meyer et al., 2005, 2006a,b,c, 2010, 2007; Nawa et al., 2000; Pearce, 2001; Tohmi et al., 2004; Urakubo et al., 2001). "
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    ABSTRACT: Schizophrenia (SCZ) is a neurodevelopmental disorder manifested symptomatically after puberty whose pharmacotherapy remains unsatisfactory. In recent years, longitudinal structural neuroimaging studies have revealed that neuroanatomical aberrations occur in this disorder and in fact precede symptom onset, raising the exciting possibility that SCZ can be prevented. There is some evidence that treatment with atypical antipsychotic drugs (APDs) prior to the development of the full clinical phenotype reduces the risk of transition to psychosis, but results remain controversial. It remains unknown whether progressive structural brain aberrations can be halted. Given the diagnostic, ethical, clinical and methodological problems of pharmacological and imaging studies in patients, getting such information remains a major challenge. Animal neurodevelopmental models of SCZ are invaluable for investigating such questions because they capture the notion that the effects of early brain damage are progressive. In recent years, data derived from such models have converged on key neuropathological and behavioral deficits documented in SCZ attesting to their strong validity, and making them ideal tools for evaluating progression of pathology following in-utero insults as well as its prevention. We review here our recent studies that use longitudinal in vivo structural imaging to achieve this aim in the prenatal immune stimulation model that is based on the association of prenatal infection and increased risk for SCZ. Pregnant rats were injected on gestational day 15 with the viral mimic polyriboinosinic-polyribocytidylic acid (poly I:C) or saline. Male and female offspring were imaged and tested behaviorally on postnatal days (PNDs) 35, 46, 56, 70 and 90. In other experiments, offspring of poly I:C- and saline-treated dams received the atypical antipsychotic drugs (APDs) clozapine or risperidone in two developmental windows: PND 34-47 and PND 48-61, and underwent behavioral testing and imaging at adulthood. Prenatal poly I:C-induced interference with fetal brain development led to aberrant postnatal brain development as manifested in structural abnormalities in the hippocampus, the striatum, the prefrontal cortex and lateral ventricles (LV), as seen in SCZ. The specific trajectories were region-, age- and sex-specific, with females having delayed onset of pathology compared to males. Brain pathology was accompanied by development of behavioral abnormalities phenotypic of SCZ, attentional deficit and hypersensitivity to amphetamine, with same sex difference. Hippocampal volume loss and LV volume expansion as well as behavioral abnormalities were prevented in the offspring of poly I:C mothers who received clozapine or risperidone during the asymptomatic period of adolescence (PND 34-47). Administration at a later window, PNDs 48-61, exerted sex-, region- and drug- specific effects. Our data show that prenatal insult leads to progressive postnatal brain pathology, which gradually gives rise to "symptoms"; that treatment with atypical APDs can prevent both brain and behavioral pathology; and that the earlier the intervention, the more pathological outcomes can be prevented.
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    • "As an additional aspect, Clarke et al. (2009) have recently reported that maternal pyelonephritis during pregnancy is associated with increased risk for schizophrenia only in persons with a positive family history of schizophrenia, suggesting a gene x environment interaction as the mechanism for increased schizophrenia risk. With respect to timing of the infection, numerous studies have identified the 2nd trimester of pregnancy as the critical period for exposure to influenza and other viral infections, leading to increased schizophrenia (Torrey et al., 1988; O'Callaghan et al., 1994; Suvisaari et al., 1999; Brown et al., 2000; Ebert and Kotler, 2005). However, the most pronounced association of rubella infection with schizophrenia spectrum disorders was found with 1st trimester exposure (Brown and Susser, 2002). "
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    ABSTRACT: Epidemiological studies with human populations indicate associations between maternal infection during pregnancy and increased risk in offspring for central nervous system (CNS) disorders including schizophrenia, autism and cerebral palsy. Since 2000, a large number of studies have used rodent models of systemic prenatal infection or prenatal immune activation to characterize changes in brain function and behavior caused by the prenatal insult. This review provides a comprehensive summary of these findings, and examines consistencies and trends across studies in an effort to provide a perspective on our current state of understanding from this body of work. Results from these animal modeling studies clearly indicate that prenatal immune activation can cause both acute and lasting changes in behavior and CNS structure and function in offspring. Across laboratories, studies vary with respect to the type, dose and timing of immunogen administration during gestation, species used, postnatal age examined and specific outcome measure quantified. This makes comparison across studies and assessment of replicability difficult. With regard to mechanisms, evidence for roles for several acute mediators of effects of prenatal immune activation has emerged, including circulating interleukin-6, increased placental cytokines and oxidative stress in the fetal brain. However, information required to describe the complete mechanistic pathway responsible for acute effects of prenatal immune activation on fetal brain is lacking, and no studies have yet addressed the issue of how acute prenatal exposure to an immunogen is transduced into a long-term CNS change in the postnatal animal. Directions for further research are discussed.
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    • "Disturbances directed at the maternal host can lead to direct physiological changes in the fetal environment when the fetus is undergoing rapid development, notably in the central nervous system. This is supported by epidemiological studies showing that maternal bacterial and viral infections during pregnancy are linked to a number of neuropsychiatric disorders with a presumed neurodevelopmental origin, including schizophrenia (Brown et al., 2004a; Mednick, Machon, Huttunen, & Bonett, 1988; O'Callaghan et al., 1994), autism (Miller et al., 2005; Rodier & Hyman, 1998) and mental retardation (Rantakallio & von Wendt, 1985; Revello & Gerna, 2004). Although the precise mechanisms underlying these epidemiological associations remain to be fully worked out, one favored hypothesis suggests that the maternal immune response to the infectious process may be the critical causative event, as the precise identity of the infectious agents do not seem to matter (Brown et al., 2004a,b; Buka et al., 2001; O'Callaghan et al.; Patterson, 2002; Pearce, 2001). "
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