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Poster #89 PRENATAL MATERNAL INFECTION, NEURODEVELOPMENT AND ADULT SCHIZOPHRENIA: A SYSTEMATIC REVIEW OF POPULATION-BASED STUDIES
Abstracts of the 3rd Biennial Schizophrenia International Research Conference / Schizophrenia Research 136, Supplement 1 (2012) S1–S375
with a significant increase in risk. In a meta-analysis involving 2,424 cases and over 1.2 million controls CNS viral infection was associated with nearly two-fold increased risk of adult non-affective psychosis (risk ratio 1.78, 95% CI 1.05- 3.02; p=0.033). Over four-fold increase in risk was observed in meta-analysis restricted to cases of schizophrenia only (risk ratio 4.41, 95% CI 1.65- 11.75; p=0.003). However, this analysis was based on relatively small numbers, 100 cases and 10,893 controls. There was no evidence of significant heterogeneity in meta-analyses. CNS bacterial infection or common childhood infections not directly affecting the CNS were not associated with increased risk of psychosis. Most studies lacked power to examine effects of specific infectious agents. However, childhood infection with mumps and cytomegalovirus was reported to increase risk of adult schizophrenic psychosis in a large Swedish cohort of over one million subjects. Coxsackie B5 virus (CBV-5) meningitis was associated with high incidence of schizophrenia in another cohort. From the published studies it was unclear infection during which stage of childhood may be more harmful. However, in the Swedish cohort there was no association between age at the time of infection and risk of adult psychosis. Findings from two birth cohorts suggest risk of adult psychotic illness following early life CNS infection may not be directly related to childhood neurological abnormalities. Discussion: These findings indicate childhood is a vulnerable period during which harmful events in respect to brain development may increase the risk of severe neuropsychiatric illnesses of adult life, such as schizophrenia. Only CNS viral infection in childhood is associated with increased risk of adult schizophrenic psychosis. Mechanisms by which CNS infections contribute to risk of adult schizophrenia may include direct neurotoxic effect by agents causing meningitis/encephalitis. It is also possible, infection in individuals with certain genetic vulnerability leads to a distinct inflammatory response leading to CNS alterations via cytokines and other mechanisms making them vulnerable to developing psychosis. Triangulation of genetic information as well as inflammatory cytokines and other immunological markers should help to elucidate the effects of early life infection on neurodevelopment, and risk of adult psychotic disorders.
Poster #89 PRENATAL MATERNAL INFECTION, NEURODEVELOPMENT AND ADULT SCHIZOPHRENIA: A SYSTEMATIC REVIEW OF POPULATION-BASED STUDIES Golam M. Khandaker 1,2 , Jorge Zimbron 1,2 , Glyn Lewis 3 , Peter B. Jones 1,2 1 University of Cambridge, Cambridge, United Kingdom; 2 Cambridgeshire and Peterborough NHS Foundation Trust, Cambridge, United Kingdom; 3 University of Bristol, Bristol, United Kingdom Background: Possible disruption of fetal development by prenatal maternal infections is in keeping with the neurodevelopmental theory of schizophrenia. Despite decades of research fundamental questions have yet to be settled. These include whether there are associations between specific types of prenatal infection and adult psychotic illness, the timing of infection, and details of particular effects on neurodevelopment. We have addressed these issues through a systematic literature review. Methods: Following electronic database (PubMed and EMBASE) and manual search, and rigorous quality assessment 21 studies were selected. Only general population-based studies that used objective assessment (serology or clinical examination) of prenatal maternal infection at the individual level, and standardised measures of schizophrenia and other psychotic outcomes in adult offspring were included. Due to variation among studies in design, exposure classification and outcome measurement we report a descriptive review. Results: The number of studies concerning risk of adult psychotic illness was 16. Five studies exclusively looked into structural and functional brain abnormalities related to schizophrenia. Included studies were based on general population cohorts from the US (National Collaborative Perinatal Project or NCPP, and Prenatal Determinants of Schizophrenia or PDS cohort), and Denmark and Finland. Birth cohort studies reported two to five-fold increased risk of schizophrenia for maternal non-specific bacterial, respiratory or genital and reproductive infections. With regards to particular infectious agents, evidence for Herpes Simplex Virus type 2 (HSV-2), Toxoplasma gondii was mixed, some studies reporting up-to two-fold increase in risk of schizophrenic psychosis. Evidence for prenatal maternal
S123
influenza was weak.No associations were found between prenatal HSV-1 or cytomegalovirus virus infection and adult psychotic illness. Most studies lacked power to address the issue of “sensitive period”; however, in general we observed a trend for greater risk of adult psychotic illness for exposure to infections during early stages of gestation. Interestingly, one study from a 1.1 million strong Danish cohort reported, maternal infection during pregnancy was not significantly different from that before or after pregnancy, in terms of increasing risk of schizophrenia in the offspring. Two studies reported associations between increased inflammatory cytokines (TNFα, IL-8) in maternal serum and risk of psychosis in adult offspring. Prenatal infection was associated with structural and functional brain abnormalities relevant to schizophrenia. Exposed cases were reported to show significant deficit in childhood and adult verbal IQ, greater IQ decline during premorbid period, and increased ventricular volume, and reduced cortical volume in adulthood. Discussion: Prenatal exposure to a range of infections and inflammatory responses may be associated with risk of adult schizophrenic psychosis. However, observed associations between schizophrenia in adult offspring and maternal infections before and after pregnancy, and exposure to several infections in the same group of case mothers (PDS and NCPP cohort), may indicate possible confounding by other factors. Future studies should use larger samples and mediation models to address the issues of “sensitive period”, and effects of prenatal infections on neurodevelopment. Inclusion of genetic and immunological information should help to elucidate to what extent genetic vulnerability to schizophrenia may be explained by vulnerability to infection.
Poster #90 AESOP-10: A 10-YEAR FOLLOW-UP STUDY OF FIRST-EPISODE PSYCHOSIS - RATIONALE, METHOD, AND PRELIMINARY FINDINGS Craig Morgan, on behalf of the AESOP-10 Study Group Institute of Psychiatry Camberwell, London, United Kingdom Background: Much research has focused on the apparent high incidence of psychosis in migrant and minority ethnic populations, and on possible explanations for this. In contrast, few studies have gone on to follow over time individuals from migrant and minority ethnic groups with a first-episode of psychosis to ascertain information on course and outcome. What studies there have been have tended to be small and findings have been inconsistent: some report a more episodic course in black groups, some report no difference. Examining ethnic variations in, and predictors of, course and outcome may also shed light on determinants of course and outcome in general. We, therefore, set out to follow at 10 years a cohort of 553 individuals with a first episode of psychosis identified in the AESOP study, with two aims: 1) to identify the factors that predict the course and outcome of psychosis following a first episode, focusing on the role of biological and social risk indicators, cannabis use, and duration of untreated psychosis (DUP); and 2) to study and explain the differences in the course and outcome of psychosis in Black and White patients. This is the first epidemiological cohort study of first episode psychosis to integrate information on clinical, biological and social predictors of outcome. Here we report initial follow-up rates by age, gender and ethnicity and preliminary indicative analyses of 10-year course of disorder. Methods: AESOP-10 is a longitudinal follow-up at 10-years of a cohort of 553 individuals with a first episode psychotic disorder initially living in south-east London and Nottingham, UK who were extensively evaluated at the time of their first episode. At 10 years, beginning with re-contact details that were recorded for cases at baseline, we sought to trace, re-contact and re-assess all cases. We also sought to conduct clinical case note reviews for all cases. Using the WHO Life Chart, we collated information on clinical course and outcome, service use and indicators of social function from clinical case records and, where possible, from follow-up interview with cases. Results: At 10 years, 438 (79%) cases were traced to their current location, 31 (6%) were known to have gone abroad, 38 (7%) had died and 46 (8%) were not traceable. There was no evidence of differences in age, gender and ethnicity by each of these outcomes, with the exception that black African cases were more likely to have moved abroad (n=14; 21%) and those aged over 30 years who were more likely to have died (n=26; 10%). Of the 438 cases successfully traced, 235 (54%) agreed to further interview,
with a significant increase in risk. In a meta-analysis involving 2,424 cases and over 1.2 million controls CNS viral infection was associated with nearly two-fold increased risk of adult non-affective psychosis (risk ratio 1.78, 95% CI 1.05- 3.02; p=0.033). Over four-fold increase in risk was observed in meta-analysis restricted to cases of schizophrenia only (risk ratio 4.41, 95% CI 1.65- 11.75; p=0.003). However, this analysis was based on relatively small numbers, 100 cases and 10,893 controls. There was no evidence of significant heterogeneity in meta-analyses. CNS bacterial infection or common childhood infections not directly affecting the CNS were not associated with increased risk of psychosis. Most studies lacked power to examine effects of specific infectious agents. However, childhood infection with mumps and cytomegalovirus was reported to increase risk of adult schizophrenic psychosis in a large Swedish cohort of over one million subjects. Coxsackie B5 virus (CBV-5) meningitis was associated with high incidence of schizophrenia in another cohort. From the published studies it was unclear infection during which stage of childhood may be more harmful. However, in the Swedish cohort there was no association between age at the time of infection and risk of adult psychosis. Findings from two birth cohorts suggest risk of adult psychotic illness following early life CNS infection may not be directly related to childhood neurological abnormalities. Discussion: These findings indicate childhood is a vulnerable period during which harmful events in respect to brain development may increase the risk of severe neuropsychiatric illnesses of adult life, such as schizophrenia. Only CNS viral infection in childhood is associated with increased risk of adult schizophrenic psychosis. Mechanisms by which CNS infections contribute to risk of adult schizophrenia may include direct neurotoxic effect by agents causing meningitis/encephalitis. It is also possible, infection in individuals with certain genetic vulnerability leads to a distinct inflammatory response leading to CNS alterations via cytokines and other mechanisms making them vulnerable to developing psychosis. Triangulation of genetic information as well as inflammatory cytokines and other immunological markers should help to elucidate the effects of early life infection on neurodevelopment, and risk of adult psychotic disorders.
Poster #89 PRENATAL MATERNAL INFECTION, NEURODEVELOPMENT AND ADULT SCHIZOPHRENIA: A SYSTEMATIC REVIEW OF POPULATION-BASED STUDIES Golam M. Khandaker 1,2 , Jorge Zimbron 1,2 , Glyn Lewis 3 , Peter B. Jones 1,2 1 University of Cambridge, Cambridge, United Kingdom; 2 Cambridgeshire and Peterborough NHS Foundation Trust, Cambridge, United Kingdom; 3 University of Bristol, Bristol, United Kingdom Background: Possible disruption of fetal development by prenatal maternal infections is in keeping with the neurodevelopmental theory of schizophrenia. Despite decades of research fundamental questions have yet to be settled. These include whether there are associations between specific types of prenatal infection and adult psychotic illness, the timing of infection, and details of particular effects on neurodevelopment. We have addressed these issues through a systematic literature review. Methods: Following electronic database (PubMed and EMBASE) and manual search, and rigorous quality assessment 21 studies were selected. Only general population-based studies that used objective assessment (serology or clinical examination) of prenatal maternal infection at the individual level, and standardised measures of schizophrenia and other psychotic outcomes in adult offspring were included. Due to variation among studies in design, exposure classification and outcome measurement we report a descriptive review. Results: The number of studies concerning risk of adult psychotic illness was 16. Five studies exclusively looked into structural and functional brain abnormalities related to schizophrenia. Included studies were based on general population cohorts from the US (National Collaborative Perinatal Project or NCPP, and Prenatal Determinants of Schizophrenia or PDS cohort), and Denmark and Finland. Birth cohort studies reported two to five-fold increased risk of schizophrenia for maternal non-specific bacterial, respiratory or genital and reproductive infections. With regards to particular infectious agents, evidence for Herpes Simplex Virus type 2 (HSV-2), Toxoplasma gondii was mixed, some studies reporting up-to two-fold increase in risk of schizophrenic psychosis. Evidence for prenatal maternal
S123
influenza was weak.No associations were found between prenatal HSV-1 or cytomegalovirus virus infection and adult psychotic illness. Most studies lacked power to address the issue of “sensitive period”; however, in general we observed a trend for greater risk of adult psychotic illness for exposure to infections during early stages of gestation. Interestingly, one study from a 1.1 million strong Danish cohort reported, maternal infection during pregnancy was not significantly different from that before or after pregnancy, in terms of increasing risk of schizophrenia in the offspring. Two studies reported associations between increased inflammatory cytokines (TNFα, IL-8) in maternal serum and risk of psychosis in adult offspring. Prenatal infection was associated with structural and functional brain abnormalities relevant to schizophrenia. Exposed cases were reported to show significant deficit in childhood and adult verbal IQ, greater IQ decline during premorbid period, and increased ventricular volume, and reduced cortical volume in adulthood. Discussion: Prenatal exposure to a range of infections and inflammatory responses may be associated with risk of adult schizophrenic psychosis. However, observed associations between schizophrenia in adult offspring and maternal infections before and after pregnancy, and exposure to several infections in the same group of case mothers (PDS and NCPP cohort), may indicate possible confounding by other factors. Future studies should use larger samples and mediation models to address the issues of “sensitive period”, and effects of prenatal infections on neurodevelopment. Inclusion of genetic and immunological information should help to elucidate to what extent genetic vulnerability to schizophrenia may be explained by vulnerability to infection.
Poster #90 AESOP-10: A 10-YEAR FOLLOW-UP STUDY OF FIRST-EPISODE PSYCHOSIS - RATIONALE, METHOD, AND PRELIMINARY FINDINGS Craig Morgan, on behalf of the AESOP-10 Study Group Institute of Psychiatry Camberwell, London, United Kingdom Background: Much research has focused on the apparent high incidence of psychosis in migrant and minority ethnic populations, and on possible explanations for this. In contrast, few studies have gone on to follow over time individuals from migrant and minority ethnic groups with a first-episode of psychosis to ascertain information on course and outcome. What studies there have been have tended to be small and findings have been inconsistent: some report a more episodic course in black groups, some report no difference. Examining ethnic variations in, and predictors of, course and outcome may also shed light on determinants of course and outcome in general. We, therefore, set out to follow at 10 years a cohort of 553 individuals with a first episode of psychosis identified in the AESOP study, with two aims: 1) to identify the factors that predict the course and outcome of psychosis following a first episode, focusing on the role of biological and social risk indicators, cannabis use, and duration of untreated psychosis (DUP); and 2) to study and explain the differences in the course and outcome of psychosis in Black and White patients. This is the first epidemiological cohort study of first episode psychosis to integrate information on clinical, biological and social predictors of outcome. Here we report initial follow-up rates by age, gender and ethnicity and preliminary indicative analyses of 10-year course of disorder. Methods: AESOP-10 is a longitudinal follow-up at 10-years of a cohort of 553 individuals with a first episode psychotic disorder initially living in south-east London and Nottingham, UK who were extensively evaluated at the time of their first episode. At 10 years, beginning with re-contact details that were recorded for cases at baseline, we sought to trace, re-contact and re-assess all cases. We also sought to conduct clinical case note reviews for all cases. Using the WHO Life Chart, we collated information on clinical course and outcome, service use and indicators of social function from clinical case records and, where possible, from follow-up interview with cases. Results: At 10 years, 438 (79%) cases were traced to their current location, 31 (6%) were known to have gone abroad, 38 (7%) had died and 46 (8%) were not traceable. There was no evidence of differences in age, gender and ethnicity by each of these outcomes, with the exception that black African cases were more likely to have moved abroad (n=14; 21%) and those aged over 30 years who were more likely to have died (n=26; 10%). Of the 438 cases successfully traced, 235 (54%) agreed to further interview,