Jones AL, Mowry BJ, Pender MP, Greer JM
Immune dysregulation and self-reactivity in schizophrenia: do some cases of schizophrenia have an autoimmune basis?
Immunol Cell Biol. 2005 Feb;83(1):9-17.
Schizophrenia affects 1% of the world's population, but its cause remains obscure. Numerous theories have been proposed regarding the cause of schizophrenia, ranging from developmental or neurodegenerative processes or neurotransmitter abnormalities to infectious or autoimmune processes. In this review, findings suggestive of immune dysregulation and reactivity to self in patients with schizophrenia are examined with reference to criteria for defining whether or not a human disease is autoimmune in origin. Associations with other autoimmune diseases and particular MHC haplotypes, increased serum levels of autoantibodies, and in vivo and in vitro replication of some of the functional and ultrastructural abnormalities of schizophrenia by transfer of autoantibodies from the sera of patients with schizophrenia suggest that, in some patients at least, autoimmune mechanisms could play a role in the development of disease. Recent findings regarding specific autoimmune responses directed against neurotransmitter receptors in the brain in patients with schizophrenia will also be reviewed. [Abstract]

Rapoport JL, Addington AM, Frangou S, Psych MR
The neurodevelopmental model of schizophrenia: update 2005.
Mol Psychiatry. 2005 May;10(5):434-49.
Neurodevelopmental models of schizophrenia that identify longitudinal precursors of illness have been of great heuristic importance focusing most etiologic research over the past two decades. These models have varied considerably with respect to specificity and timing of hypothesized genetic and environmental 'hits', but have largely focused on insults to prenatal brain development. With heritability around 80%, nongenetic factors impairing development must also be part of the model, and any model must also account for the wide range of age of onset. In recent years, longitudinal brain imaging studies of both early and adult (to distinguish from late ie elderly) onset populations indicate that progressive brain changes are more dynamic than previously thought, with gray matter volume loss particularly striking in adolescence and appearing to be an exaggeration of the normal developmental pattern. This supports an extended time period of abnormal neurodevelopment in schizophrenia in addition to earlier 'lesions'. Many subtle cognitive, motor, and behavioral deviations are seen years before illness onset, and these are more prominent in early onset cases. Moreover, schizophrenia susceptibility genes and chromosomal abnormalities, particularly as examined for early onset populations (ie GAD1, 22q11DS), are associated with premorbid neurodevelopmental abnormalities. Several candidate genes for schizophrenia (eg dysbindin) are associated with lower cognitive abilities in both schizophrenic and other pediatric populations more generally. Postmortem human brain and developmental animal studies document multiple and diverse effects of developmental genes (including schizophrenia susceptibility genes), at sequential stages of brain development. These may underlie the broad array of premorbid cognitive and behavioral abnormalities seen in schizophrenia, and neurodevelopmental disorders more generally. Increased specificity for the most relevant environmental risk factors such as exposure to prenatal infection, and their interaction with susceptibility genes and/or action through phase-specific altered gene expression now both strengthen and modify the neurodevelopmental theory of schizophrenia. [Abstract]

Hanson DR, Gottesman II
Theories of schizophrenia: a genetic-inflammatory-vascular synthesis.
BMC Med Genet. 2005 Feb 11;6(1):7.
BACKGROUND: Schizophrenia, a relatively common psychiatric syndrome, affects virtually all brain functions yet has eluded explanation for more than 100 years. Whether by developmental and/or degenerative processes, abnormalities of neurons and their synaptic connections have been the recent focus of attention. However, our inability to fathom the pathophysiology of schizophrenia forces us to challenge our theoretical models and beliefs. A search for a more satisfying model to explain aspects of schizophrenia uncovers clues pointing to genetically mediated CNS microvascular inflammatory disease. DISCUSSION: A vascular component to a theory of schizophrenia posits that the physiologic abnormalities leading to illness involve disruption of the exquisitely precise regulation of the delivery of energy and oxygen required for normal brain function. The theory further proposes that abnormalities of CNS metabolism arise because genetically modulated inflammatory reactions damage the microvascular system of the brain in reaction to environmental agents, including infections, hypoxia, and physical trauma. Damage may accumulate with repeated exposure to triggering agents resulting in exacerbation and deterioration, or healing with their removal.There are clear examples of genetic polymorphisms in inflammatory regulators leading to exaggerated inflammatory responses. There is also ample evidence that inflammatory vascular disease of the brain can lead to psychosis, often waxing and waning, and exhibiting a fluctuating course, as seen in schizophrenia. Disturbances of CNS blood flow have repeatedly been observed in people with schizophrenia using old and new technologies. To account for the myriad of behavioral and other curious findings in schizophrenia such as minor physical anomalies, or reported decreased rates of rheumatoid arthritis and highly visible nail fold capillaries, we would have to evoke a process that is systemic such as the vascular and immune/inflammatory systems. SUMMARY: A vascular-inflammatory theory of schizophrenia brings together environmental and genetic factors in a way that can explain the diversity of symptoms and outcomes observed. If these ideas are confirmed, they would lead in new directions for treatments or preventions by avoiding inducers of inflammation or by way of inflammatory modulating agents, thus preventing exaggerated inflammation and consequent triggering of a psychotic episode in genetically predisposed persons. [Abstract]

Rothermundt M, Arolt V, Bayer TA
Review of immunological and immunopathological findings in schizophrenia.
Brain Behav Immun. 2001 Dec;15(4):319-39.
The involvement of immunological and immunopathological mechanisms in the etiopathogenesis of schizophrenia has been a matter of research, with recently increasing effort. This article reviews the findings focusing on postmortem neuropathology, the blood-brain barrier, antibodies, acute phase proteins, immunocompetent cells, and activation markers of immunocompetent cells. Evidence for the two primarily postulated hypotheses (the infectious hypothesis and the autoimmune hypothesis) is critically discussed. On the basis of the findings, perspectives for future research are outlined aiming at a precise and consequent strategy to elucidate a potential involvement of immune mechanisms in the etiopathogenesis of schizophrenia. [Abstract]

Wright P, Sham PC, Gilvarry CM, Jones PB, Cannon M, Sharma T, Murray RM
Autoimmune diseases in the pedigrees of schizophrenic and control subjects.
Schizophr Res. 1996 Jul 5;20(3):261-7.
Autoimmune diseases aggregate in individuals and within pedigrees, and it has been postulated that autoimmune mechanisms may account for a proportion of schizophrenia. Structured questionnaires were used to interview the mothers of 121 DSM-III-R schizophrenic patients and the mothers of 116 controls in order to determine the prevalence of schizophrenia and of autoimmune diseases in their pedigrees. Patients with a schizophrenic first degree relative were significantly more likely to also have a parent or sibling with an autoimmune disease (60% vs. 20%, OR = 6.1, 95% CI = 2.3-6.5, p = 0.0003). A significant excess of insulin dependent diabetes mellitus (IDDM) was present in the parents and siblings of schizophrenic patients (OR = 9.65, 95% CI = 1.3-429.2, p = 0.009). These findings suggest that autoimmune mechanisms may play a role in the aetiology of schizophrenia, particularly familial schizophrenia. Associations have been established between autoimmune diseases and the HLA encoding genes of the major histocompatibility complex on chromosome six, and it may be that some of the genetic liability to schizophrenia involves these genes. [Abstract]

Gilvarry CM, Sham PC, Jones PB, Cannon M, Wright P, Lewis SW, Bebbington P, Toone BK, Murray RM
Family history of autoimmune diseases in psychosis.
Schizophr Res. 1996 Mar;19(1):33-40.
The mothers of 101 psychotic patients and 116 normal controls were interviewed using a semi-structured questionnaire designed to determine the presence or absence of autoimmune disorders in first degree relatives of the probands. Thyrotoxicosis and insulin-dependent diabetes mellitus were significantly more common in the relatives of the psychotic patients than in the control relatives; in particular thyrotoxicosis was more frequent in the mothers of patients (11%) than the mothers of controls (2.6%). None of the examined characteristics of the patients, including RDC-diagnosis, family history of psychosis, age at onset of psychosis and winter birth, was predictive of thyrotoxicosis and insulin-dependent diabetes mellitus in relatives. [Abstract]

Levine J, Gutman J, Feraro R, Levy P, Kimhi R, Leykin I, Deckmann M, Handzel ZT, Shinitzky M
Side effect profile of azathioprine in the treatment of chronic schizophrenic patients.
Neuropsychobiology. 1997;36(4):172-6.
Various findings suggest auto-immune changes in schizophrenia. We have recently demonstrated that platelets from schizophrenic patients bear autoantibodies (PAA) which cross-react with brain antigens. Accordingly, treatment of schizophrenia with an immunosuppressant might be of potential benefit. In a recent case study, a chronic schizophrenic patient treated with azathioprine has demonstrated a clear psychiatric improvement preceded by a decrease in PAA level. A phase I study designed for assessing side-effects of short-term azathioprine treatment in a group of schizophrenic patients is described here. From a group of 40 chronic non-responsive patients, 14 patients demonstrating high PAA level have entered the study and 11 have complied all along. Two groups were tested in parallel. In the first (6 patients) 150 mg/day was given for 7 weeks while in the second (5 patients) the same regimen was given for two periods of 7 weeks with an interval of 6 weeks. Blood biochemistry and cell count, as well as determination of PAA were carried out weekly, starting 3 weeks before the trial and continuing up to 7 weeks after the treatment. Two out of 11 patients developed leucopenia in week 4. No other side-effects were recorded in any of the patients. A substantial reduction in PAA was observed in 3 out of 6 patients in group I and 4 out of 5 in group II. Two patients showed improvement of psychiatric symptomatology. Our results demonstrate that short-term azathioprine treatment induces transient leucopenia in 18% of the patients receiving the drug, much alike the percentage reported for other patient populations. [Abstract]

Fuller Torrey E, Yolken RH
Familial and genetic mechanisms in schizophrenia.
Brain Res Brain Res Rev. 2000 Mar;31(2-3):113-7.
A distinction should be made between genetic aspects of schizophrenia and familial aspects. Genetic aspects of the disease have been reviewed and found to be deficient in many respects. Until recent years, familial factors were assumed to be psychological in origin, but this assumption is now discredited. Research efforts should focus on familial factors that are biological, especially infectious agents that may be transmitted within the family. Most infectious agents are influenced by predisposing genes. The etiology of schizophrenia, then, may turn out to involve biological familial infectious agents that are influenced by susceptibility genes governing the infectious process and the clinical expression of the disease. [Abstract]

Tsuang M
Schizophrenia: genes and environment.
Biol Psychiatry. 2000 Feb 1;47(3):210-20.
The historical and genetic foundations of our current understanding of schizophrenia are reviewed, as are the present and future directions for research. Genetic epidemiological investigations, including family, twin, and adoption studies have confirmed the contributions of genetic and environmental determinants of schizophrenia. For example, identical twins show average concordance rates of only 50%; rates of 100% would be expected on the basis of genetic equivalence alone. Genetic factors may cause errors in brain development and synaptic connections. A broad range of environmental components may further damage the brain. Biological components may include pregnancy and delivery complications, such as intrauterine fetal hypoxia, infections, and malnutrition. Primarily nonbiological components may include psychosocial stressors, such as residence in an urban area and dysfunctional family communication. It is likely that the environmental factors interact with the genetic liability in a negative manner to produce disorders in the schizophrenic spectrum. Genetic and environmental components of the disorder are examined, as well as their interactions in producing either neurodevelopmental syndromes or schizophrenia itself. The implication of these findings for prevention and treatment are considered. [Abstract]

Davis JO, Phelps JA, Bracha HS
Prenatal development of monozygotic twins and concordance for schizophrenia.
Schizophr Bull. 1995;21(3):357-66.
While twin concordances for schizophrenia have been used to estimate heritability and to develop genetic models, concordances in subtypes of monozygotic (MZ) twins can also be used to investigate the influence of prenatal development in the etiology of mental illness. We used within-pair variability and mirroring of fingerprints to estimate retrospectively the placentation status of concordant and discordant MZ twins. The results indicate that concordant MZ pairs were more likely to have been monochorionic (MC) and to have shared a single placenta, whereas discordant MZ pairs appear more likely to have been dichorionic (DC) with separate placentas. Pairwise concordances for MZ twins without MC markers averaged 10.7 percent. In contrast, concordances for MZ twins with one or more MC markers averaged 60 percent. This suggests that simple MZ concordance rates may overestimate schizophrenia heritability and that prenatal development may also be important in the etiology of schizophrenia. Because MC (but not DC) twins usually share fetal blood circulation and hence are likely to share infections, these results are consistent with the hypothesis that fetal infections may be a significant etiological factor in schizophrenia. [Abstract]

Torrey EF, Taylor EH, Bracha HS, Bowler AE, McNeil TF, Rawlings RR, Quinn PO, Bigelow LB, Rickler K, Sjostrom K
Prenatal origin of schizophrenia in a subgroup of discordant monozygotic twins.
Schizophr Bull. 1994;20(3):423-32.
Neuropathological, obstetrical, and epidemiological evidence increasingly suggest that some cases of adult-onset schizophrenia have prenatal or neonatal etiological roots. We evaluated the developmental histories of 23 monozygotic twin pairs discordant for schizophrenia to determine when they markedly and permanently began diverging from each other in motor skills or unusual behavior. Seven of the twins (30%) who later developed schizophrenia had become permanently different from their cotwins by age 5 years. The early divergence group differed from the others by multivariate tests (p = 0.002) for within-twin pair effects and by univariate tests for physical anomaly scores (p = 0.01), total finger ridge counts (p = 0.001), family history of psychosis (p = 0.004), and serious perinatal complications or low birth weight (p = 0.05). It is concluded that some cases of adult-onset schizophrenia are associated with prenatal events, which may include neurodevelopmental abnormalities or specific insults such as anoxia or infectious agents. [Abstract]

Brown AS, Begg MD, Gravenstein S, Schaefer CA, Wyatt RJ, Bresnahan M, Babulas VP, Susser ES
Serologic evidence of prenatal influenza in the etiology of schizophrenia.
Arch Gen Psychiatry. 2004 Aug;61(8):774-80.
CONTEXT: Some, but not all, previous studies suggest that prenatal influenza exposure increases the risk of schizophrenia. These studies used dates of influenza epidemics and maternal recall of infection to define influenza exposure, suggesting that discrepant findings may have resulted from exposure misclassification. OBJECTIVE: To examine whether serologically documented prenatal exposure to influenza increases the risk of schizophrenia. DESIGN: Nested case-control study of a large birth cohort, born from 1959 through 1966, and followed up for psychiatric disorders 30 to 38 years later. SETTING: Population-based birth cohort. PARTICIPANTS: Cases were 64 birth cohort members diagnosed as having schizophrenia spectrum disorders (mostly schizophrenia and schizoaffective disorder). Controls were 125 members of the birth cohort, had not been diagnosed as having a schizophrenia spectrum or major affective disorder, and were matched to cases on date of birth, sex, length of time in the cohort, and availability of maternal serum. MAIN OUTCOME MEASURES: Archived maternal serum was assayed for influenza antibody in pregnancies giving rise to offspring with schizophrenia and matched control offspring. RESULTS: The risk of schizophrenia was increased 7-fold for influenza exposure during the first trimester. There was no increased risk of schizophrenia with influenza during the second or third trimester. With the use of a broader gestational period of influenza exposure-early to midpregnancy-the risk of schizophrenia was increased 3-fold. The findings persisted after adjustment for potential confounders. CONCLUSIONS: These findings represent the first serologic evidence that prenatal influenza plays a role in schizophrenia. If confirmed, the results may have implications for the prevention of schizophrenia and for unraveling pathogenic mechanisms of the disorder. [Abstract]

Takei N, Lewis S, Jones P, Harvey I, Murray RM
Prenatal exposure to influenza and increased cerebrospinal fluid spaces in schizophrenia.
Schizophr Bull. 1996;22(3):521-34.
Several epidemiological studies have suggested that maternal exposure to influenza during midgestation is a risk factor for schizophrenia. In exploring the possible pathogenic mechanism, we examined the relationship between computed tomography structural brain measures in 83 schizophrenia patients and 113 controls and also their risk of maternal exposure to influenza. Four brain measures of the cerebrospinal fluid (CSF) spaces (lateral ventricle, maximum third ventricle, sulcal fluid, and sylvian fissure) were investigated in relation to the risk exposure level. In schizophrenia patients, these measures, in particular sylvian fissures, were found to increase with higher levels of risk exposure to influenza during the susceptible period (i.e., midgestation); no such effect was found in controls. These results indicate that risk for midgestational influenza exposure is associated with generalized enlargement of the CSF spaces, especially in the region of the temporal lobe. The findings suggest that certain morphological abnormalities of the brain frequently reported in schizophrenia patients may be partly attributable to antenatal exposure to influenza. [Abstract]

Limosin F, Rouillon F, Payan C, Cohen JM, Strub N
Prenatal exposure to influenza as a risk factor for adult schizophrenia.
Acta Psychiatr Scand. 2003 May;107(5):331-5.
OBJECTIVE: Several, but not all epidemiological studies, have demonstrated a positive correlation between exposure to the virus during the second trimester of pregnancy and an increased risk to the infants for subsequently developing schizophrenia. The present study is the first be designed in France to examine the risk of gestational exposure to the influenza virus and subsequent development of schizophrenia. METHOD: A total of 974 adults with schizophrenia born between 1949 and 1981 were compared for risk of exposure to influenza with their non-schizophrenic siblings and with matched control patients. RESULTS: Significantly more schizophrenic subjects than controls (both groups) had been exposed to the influenza virus during the fifth month of pregnancy (OR=2.24, CI: 1.49-3.35, and OR=1.61, CI: 1.04-2.49). CONCLUSION: These results suggest that influenza infection during pregnancy is a neurodevelopmental risk factor for schizophrenia in adult life. [Abstract]

Bembenek A
[Does the foetus exposition on influenza infection may increase the risk of schizophrenia in adult life?]
Psychiatr Pol. 2005 Mar-Apr;39(2):271-83.
INTRODUCTION: Epidemiological studies indicate the existence of various environmental factors, which elevate the risk of schizophrenia in adult life. Influenza infection is a widely discussed causal factor in the relation to schizophrenia. The paper is a review of the studies on the theme of exposition to viral infections in foetal life--in connection with schizophrenia morbidity in adult life. Many of such studies, and yet not all of them show such a relationship. AIM: The aim of our study was to find the effect of influenza exposition in foetal life on the increase in schizophrenia morbidity of the Polish population, by applying the seasonal decomposition method. METHOD: All persons discharged from hospitals in Poland with a diagnosis of schizophrenia in the years 1997-2000 were taken up for the study. The data on the population births in the given months of the period 1964-1984 was also used. Monthly indices of the number of births of patients with a diagnosis of schizophrenia per 10,000 live births in the general population of men and women was applied in order to eliminate the seasonal variability due to the unstable number of births in the general population. The number of influenza cases in Poland was divided by the number of inhabitants and multiplied by 10,000 thus forming indices of influenza cases in the subsequent months of the period studied. The seasonal decomposition method--Census I--was used for the basic analyses--this being one of the methods of time interval analyses available in the Statistica programme. RESULTS: The study results show that exposition to influenza infections 2-4 months prior to birth may be a risk factor in schizophrenia development in adult life. [Abstract]

Wright P, Takei N, Rifkin L, Murray RM
Maternal influenza, obstetric complications, and schizophrenia.
Am J Psychiatry. 1995 Dec;152(12):1714-20.
OBJECTIVE: Epidemiologic studies have reported an association between prenatal exposure to influenza and adult schizophrenia. The authors studied this association in individual patients with schizophrenia and also investigated the relationship of obstetric complications, another postulated risk factor, to adult schizophrenia. METHOD: Using a structured interview instrument, the authors assessed infections during pregnancy, obstetric complications, gestational age, and birth weight by interviewing the mothers of 121 patients with DSM-III-R schizophrenia. RESULTS: Significantly more infections were reported in the second trimester of the patients' gestations than in the combined first and third trimesters. Influenza accounted for 70% of second-trimester infections. Patients with schizophrenia whose mothers reported having influenza during the second trimester were almost five times more likely to experience at least one definite obstetric complication than were patients who were not exposed to influenza during the second trimester; the exposed patients weighed a mean of 210 g less at birth than the unexposed patients. CONCLUSIONS: Maternal influenza during the second trimester may impair fetal growth and predispose to obstetric complications and lower birth weight in a proportion of individuals destined to develop schizophrenia. [Abstract]

Voldsgaard P, Schiffman J, Mednick S, Rodgers B, Christensen H, Bredkjaer S, Schulsinger F
Accuracy of retrospective reports of infections during pregnancy.
Int J Methods Psychiatr Res. 2002;11(4):184-6.
A large body of research suggests a relationship between maternal influenza and the development of schizophrenia in the adult offspring. Some researchers, however, have questioned this association. A study by Crow and Done (1992) asserts that prenatal exposure to influenza does not cause schizophrenia. The methodology employed by Crow and Done may account for their null findings. Crow and colleagues assessed influenza by asking mothers at the time of birth to recall influenza infections experienced during pregnancy. Such retrospective recall may bias reporting. We assessed influenza symptoms during pregnancy in a group of 136 mothers at the twenty-fifth week of pregnancy, and again one or two days after birth. We compared accounts of influenza at the twenty-fifth week to recollection of influenza after birth. Results suggest that mothers tend to under-report infections when recalling infections after birth. Retrospective assessment of influenza symptoms at birth may be an inaccurate method of assessing influenza during pregnancy. [Abstract]

Westergaard T, Mortensen PB, Pedersen CB, Wohlfahrt J, Melbye M
Exposure to prenatal and childhood infections and the risk of schizophrenia: suggestions from a study of sibship characteristics and influenza prevalence.
Arch Gen Psychiatry. 1999 Nov;56(11):993-8.
BACKGROUND: It has been proposed that infections, perhaps prenatal exposure to the influenza virus, might increase the risk of schizophrenia. To address this hypothesis, we studied the possible influence on schizophrenia risk of sibship characteristics and ecological influenza prevalence data. Birth order and influenza prevalence were used as proxy measures for exposure to prenatal infection, and sibship size and interval to siblings were used as proxy measures for exposure to common childhood infections. METHODS: We established a population-based cohort of 1746366 persons whose mothers were Danish-born women born since 1935 by using data from the Civil Registration System. Schizophrenia in cohort members (n = 2669) and their parents was identified by linkage with the Danish Psychiatric Case Register. Birth order, sibship size, and interval to siblings were calculated for each cohort member based on person-identifiable information on all siblings. The number of notifications of influenza per month in Denmark was obtained from the National Board of Health and Statens Serum Institut. RESULTS: There was no association between birth order and schizophrenia risk or between schizophrenia risk and influenza prevalence during any month of prenatal life. Coming from a large sibship was associated with an increased schizophrenia risk. The relative risks were 1.26 (95% confidence interval [CI], 1.11-1.44) and 1.46 (95% CI, 1.22-1.75) for sibships of 4 and 5 or more, respectively, vs. a sibship of 2. Short interval (<2 years) to the nearest older sibling and nearest younger sibling was associated with a risk of 1.22 (95% CI, 1.05-1.38) and 1.15 (95% CI, 1.03-1.28), respectively, compared with longer intervals. CONCLUSIONS: Our findings do not support the hypothesis that schizophrenia is associated with prenatal exposure to common infections or influenza. However, they are compatible with the hypothesis that environmental exposure, perhaps to common infections in childhood, may be a risk factor, although other explanations are also possible. [Abstract]

Sham PC, MacLean CJ, Kendler KS
Risk of schizophrenia and age difference with older siblings. Evidence for a maternal viral infection hypothesis?
Br J Psychiatry. 1993 Nov;163627-33.
Recent reports that some influenza epidemics may be followed by a transient increase in the births of schizophrenic patients have led to the hypothesis that maternal viral infections contribute to the aetiology of schizophrenia. It is well known that respiratory viral infections are frequently brought into the home by young children. We tested the predictions that the risk of schizophrenia is decreased in first-born children, and increased in individuals who had siblings of a young age while in utero, using data from a Swedish family study. Our results are consistent with these predictions. In particular, having siblings three to four years older was associated with a significantly increased risk of schizophrenia, even after allowing for birth order, sibship size, and other potential confounders. If replicated, these results provide indirect support for the maternal viral infection hypothesis, although there are alternative explanations. [Abstract]

Takei N, Mortensen PB, Klaening U, Murray RM, Sham PC, O'Callaghan E, Munk-Jørgensen P
Relationship between in utero exposure to influenza epidemics and risk of schizophrenia in Denmark.
Biol Psychiatry. 1996 Nov 1;40(9):817-24.
Several recent epidemiological studies suggest that exposure to influenza during gestation increases the risk of later developing schizophrenia. Inconsistency exists, however, particularly in studies that have examined the relationship between the prevalence of influenza and the monthly number of schizophrenic births, over many years. Our sample (N = 9462) was obtained from a Danish computerized case register, and consisted of schizophrenia patients born between 1915 and 1970, and first admitted to Danish psychiatric hospitals between 1971 and 1991. The study sample was chosen to represent "incidence cases" to allow us to calculate the population attributable risk fraction (PAF). The temporal correlation of fluctuations in the prevalence of influenza and fluctuations in the monthly number of preschizophrenic births was examined using a Poisson regression analysis. Exposure to influenza 4 months prior to birth (i.e., about the 6th month of gestation) was significantly associated with an increased risk of later schizophrenia, especially for narrowly defined schizophrenia. The number of schizophrenic births was found to have risen by 12% (95% confidence interval: 1-24%) for every 100,000 cases of influenza in the 4th month before birth. Our model indicates the PAF to be 1.4%, that is, only 1.4% of the whole schizophrenic sample is attributed to prenatal exposure to influenza. Although maternal exposure to influenza during midgestation is not a major risk factor for schizophrenia, the elucidation of its causal mechanism may open the avenue to understanding the neurodevelopmental origins of the disease. [Abstract]

Barr CE, Mednick SA, Munk-Jorgensen P
Exposure to influenza epidemics during gestation and adult schizophrenia. A 40-year study.
Arch Gen Psychiatry. 1990 Sep;47(9):869-74.
We attempted to replicate earlier findings of an association between exposure to influenza in the second trimester of gestation and adult schizophrenia. The number of live births, of births of future schizophrenics, and of cases of influenza reported to the Ministry of Health in Denmark was ascertained by month from 1911 to 1950. The relationship between fetal exposure to influenza and adult schizophrenia was examined. It is possible that unknown factors produce excesses of both influenza and schizophrenia in the winter, creating an artifactual association. To control for this coincidence, the effects of season were removed from the monthly influenza and schizophrenic birth-rates by several methods. Using the residual scores, it was found that influenza rates higher than seasonally expected, occurring in the sixth month of gestation, were associated with rates of births of schizophrenics greater than seasonally expected. This association was not attributable to some winter-related, third factor or to climatic variables. [Abstract]

Machón RA, Huttunen MO, Mednick SA, Sinivuo J, Tanskanen A, Bunn Watson J, Henriksson M, Pyhälä R
Adult schizotypal personality characteristics and prenatal influenza in a Finnish birth cohort.
Schizophr Res. 2002 Mar 1;54(1-2):7-16.
Recent evidence suggests that schizophrenia may result from a disruption of normal brain development during a critical, prenatal risk period in the 6th month of gestation. The phenotypic diagnostic manifestation of a basic genetic-neurodevelopmental disorder may consist of characteristics approximated by the DSM-IV diagnosis of "schizotypal personality disorder" (SPD). We identified male conscripts in Finland who, as fetuses, were exposed to the 1969 Hong Kong Influenza epidemic, along with a group of controls born during a relatively low year (1971) for infectious epidemics. It was hypothesized that among fetuses exposed to the influenza epidemic in their 6th month of gestation, we would observe an increased frequency of elevated (upper quartile) scores on a schizotypal personality characteristics (SPC) scale as compared to controls. A significantly higher proportion of the 6th month index exposed subjects (39%) had "elevated" SPC scale scores as compared to their controls (26%) (p<0.003). Further analyses revealed that these differences were accounted for by those exposed to the influenza epidemic in week 23 (51% vs. 24%) of the 6th month (p<0.005). Exploratory analyses for the other months did not reveal any significant differences. Implications and limitations of the week 23 findings are discussed. [Abstract]

Mednick SA, Machon RA, Huttunen MO, Bonett D
Adult schizophrenia following prenatal exposure to an influenza epidemic.
Arch Gen Psychiatry. 1988 Feb;45(2):189-92.
In the context of a Finnish birth cohort, we tested the hypothesis that viral infection during the latter two thirds of fetal development would increase the risk of adult schizophrenic outcome. Psychiatric hospital diagnoses were recorded for all individuals in greater Helsinki who were fetuses during the 1957 type A2 influenza epidemic. Those exposed to the viral epidemic during their second trimester of fetal development were at elevated risk of being admitted to a psychiatric hospital with a diagnosis of schizophrenia. This was true for both males and females and independently in several psychiatric hospitals. The second-trimester effect was seen in the elevated proportion of schizophrenics among those admitted to a psychiatric hospital and also in higher rates of schizophrenia per 1000 live births in the city of Helsinki. The study has several limitations: (1) We have no direct evidence that the subjects actually suffered a viral infection. (2) The psychiatric data were obtained only for subjects up to the age of 26 years, 56 days. (3) The findings are based on hospital diagnoses. (4) The determination of stage of gestation at time of exposure to the epidemic is based on date of birth. The viral infection might have occurred outside the official epidemic window; the infant may have had a preterm or postterm delivery. These sources of error, however, should not serve to enhance the findings. The observed viral effect is interpreted as being one of many potential perturbations of gestation. We suggest that it is less the type than the timing of the disturbance during fetal neural development that is critical in determining risk for schizophrenia. [Abstract]

Cooper SJ
Schizophrenia after prenatal exposure to 1957 A2 influenza epidemic.
Br J Psychiatry. 1992 Sep;161394-6.
"The birth dates of schizophrenic inpatients in eight health regions in England and Wales were reviewed for any effect of the 1957 A2 influenza epidemic. 5 months after the peak infection prevalence, the number of births of individuals who later developed schizophrenia was 88% higher than the average number of such births in the corresponding periods of the 2 previous and the next 2 years. This finding is in accordance with a study from Helsinki and with clinical and neuropathological evidence of aberrant fetal brain development in the pathogenesis of schizophrenia." [Abstract]

Sham PC, O'Callaghan E, Takei N, Murray GK, Hare EH, Murray RM
Schizophrenia following pre-natal exposure to influenza epidemics between 1939 and 1960.
Br J Psychiatry. 1992 Apr;160461-6.
We examined the relationship between the dates of births of schizophrenic patients admitted to hospitals for the first time in England and Wales between 1970 and 1979, and the occurrence of influenza epidemics between 1939 and 1960. Our results indicate that exposure to influenza epidemics between the third and seventh month of gestation is associated with schizophrenia in adult life. The hypothesis that maternal viral infection is an important cause of schizophrenia can explain many aspects of the enigmatic epidemiology of the condition. [Abstract]

Crow TJ, Done DJ
Prenatal exposure to influenza does not cause schizophrenia.
Br J Psychiatry. 1992 Sep;161390-3.
Claims have been made that maternal infection with influenza during pregnancy is a cause of schizophrenia in the child. These assertions are based upon some apparently significant associations between the timing of influenza epidemics in the general population and birth rates of people who later suffered from schizophrenia. Such associations have not been present in studies of the 1919 and 1957 epidemics, with sample sizes larger than those on which the claims were made. More decisively, in an investigation of the subsequent psychiatric admissions of people born a few months after the 1957 epidemic, it was found that the children of 945 mothers who actually suffered from influenza during the second trimester of pregnancy were at no greater risk of developing schizophrenia than children of mothers who were not infected. In contrast to the predictions of the influenza hypothesis of 26.5 extra cases by broad diagnostic criteria and 15.8 cases by narrow criteria, the numbers observed in children of mothers exposed to influenza in the second trimester were 3 and 1 cases respectively, close to the expected rate. It is concluded that prenatal influenza and schizophrenia are unrelated. [Abstract]

McGrath JJ, Pemberton MR, Welham JL, Murray RM
Schizophrenia and the influenza epidemics of 1954, 1957 and 1959: a southern hemisphere study.
Schizophr Res. 1994 Dec;14(1):1-8.
The dates of birth of patients who were admitted with schizophrenia to public hospitals in Queensland between the years 1972 and 1988 were examined for associations between risk of schizophrenia and influenza epidemics. The hypothesis that infants born between four and six months after an influenza epidemic onset have increased risk of schizophrenia was examined for the 1954, 1957 and 1959 epidemics. After the 1954 epidemic there was a significant excess of male schizophrenia births four months after the onset of the epidemic. In 1957, there was a significant excess of female schizophrenia births in the fifth month after the onset of the epidemic. The 1959 epidemic was not associated with any significant excess. [Abstract]

Adams W, Kendell RE, Hare EH, Munk-Jørgensen P
Epidemiological evidence that maternal influenza contributes to the aetiology of schizophrenia. An analysis of Scottish, English, and Danish data.
Br J Psychiatry. 1993 Oct;163522-34.
The epidemiological evidence that the offspring of women exposed to influenza in pregnancy are at increased risk of schizophrenia is conflicting. In an attempt to clarify the issue we explored the relationship between the monthly incidence of influenza (and measles) in the general population and the distribution of birth dates of three large series of schizophrenia patients--16,960 Scottish patients born in 1932-60; 22,021 English patients born in 1921-60; and 18,723 Danish patients born in 1911-65. Exposure to the 1957 epidemic of A2 influenza in midpregnancy was associated with an increased incidence of schizophrenia, at least in females, in all three data sets. We also confirmed the previous report of a statistically significant long-term relationship between patients' birth dates and outbreaks of influenza in the English series, with time lags of -2 and -3 months (the sixth and seventh months of pregnancy). Despite several other negative studies by ourselves and others we conclude that these relationships are probably both genuine and causal; and that maternal influenza during the middle third of intrauterine development, or something closely associated with it, is implicated in the aetiology of some cases of schizophrenia. [Abstract]

Kendell RE, Kemp IW
Maternal influenza in the etiology of schizophrenia.
Arch Gen Psychiatry. 1989 Oct;46(10):878-82.
There are epidemiological reasons for suspecting that infections may contribute to the etiology of schizophrenia, and it is claimed that the birth cohort that was in utero during the 1957 influenza epidemic in Helsinki, Finland, now has an increased incidence of schizophrenia. Three studies, all based on the admission statistics of Scottish psychiatric hospitals, were therefore undertaken to determine whether those who were in utero during the influenza A epidemics of 1918 to 1919 and 1957 were subsequently at increased risk of schizophrenia. Edinburgh data suggest that those who were in the sixth month of intrauterine development during the 1957 epidemic were subsequently at increased risk, but Scottish national data do not reveal any increased risk associated with either the 1918 to 1919 or 1957 epidemics. Overall, the hypothesis that maternal influenza may contribute to the etiology of schizophrenia is not supported, but the possibility cannot yet be discounted. [Abstract]

Cannon M, Cotter D, Coffey VP, Sham PC, Takei N, Larkin C, Murray RM, O'Callaghan E
Prenatal exposure to the 1957 influenza epidemic and adult schizophrenia: a follow-up study.
Br J Psychiatry. 1996 Mar;168(3):368-71.
BACKGROUND. We investigated the hypothesis that prenatal exposure to the 1957 A2 influenza increases the risk of schizophrenia in adulthood. METHOD. We traced a cohort of individuals known to have been exposed to the 1957 influenza epidemic during gestation and an unexposed cohort matched for period of gestation and hospital of birth. Follow-up information on psychiatric illness in subjects was sought from two sources: maternal interview and psychiatric hospital admission data. RESULTS. Follow-up information was obtained on 54% of the sample: 238 subjects from the influenza-exposed group and 287 subjects from the unexposed group. There was no increased risk of schizophrenia among the exposed cohort compared to the unexposed cohort (relative risk 1.1; 95% Cl 0.41-2.95), although there was an increase in depressive illness (relative risk 1.59; 95% Cl 1.15-2.19). CONCLUSIONS. The association between prenatal influenza and an increased risk of schizophrenia in adulthood has thus far been found only in population-based data and is not supported by the present observational study which has information about exposure and outcome in individuals. [Abstract]

Izumoto Y, Inoue S, Yasuda N
Schizophrenia and the influenza epidemics of 1957 in Japan.
Biol Psychiatry. 1999 Jul 1;46(1):119-24.
BACKGROUND: We tested the hypothesis that the exposure to an influenza epidemic during the second trimester of gestation is associated with an increased risk of later development of schizophrenia. METHODS: There were three influenza epidemics (A/B mixed type, the first A2 type and the second A2 type) in 1957 in Kochi, Japan. We compared the risk of developing schizophrenia in birth cohorts exposed to these three influenza epidemics during gestation with that in birth cohorts not exposed. To identify subjects who had developed schizophrenia, we surveyed patients with schizophrenia who received medical care at all psychiatric institutions in Kochi prefecture. RESULTS: There is a pattern that schizophrenic births increase twice or more among female subjects who were exposed to each of three influenza epidemics in the fifth month of gestation. The increase in the female births exposed to the second A2 epidemic was significant (relative risk 2.86, 95% confidence interval 1.37-5.26). This pattern across the three epidemics was not observed in male subjects. CONCLUSIONS: Prenatal exposure to an influenza epidemic during the second trimester increased the risk of later development of schizophrenia in female births. [Abstract]

Kunugi H, Nanko S, Takei N, Saito K, Hayashi N, Kazamatsuri H
Schizophrenia following in utero exposure to the 1957 influenza epidemics in Japan.
Am J Psychiatry. 1995 Mar;152(3):450-2.
OBJECTIVE: Studies in Finland, England, and Denmark have reported that individuals exposed to the 1957 A2 influenza pandemic during their second trimester in utero are at greater risk for later schizophrenia. However, other studies in England, the United States, and Holland reported no such association. The authors' goal was to shed light on these conflicts. METHOD: They compared the number of individuals who later developed schizophrenia who were born in the 5 months after the peak prevalence of three distinct 1957 influenza epidemics in Japan with the mean number of individuals who later developed schizophrenia who were born in the corresponding months of the 4 years surrounding the epidemics. RESULTS: A significantly greater number of females but not males who later developed schizophrenia were born during the risk exposure months than in the non-risk-exposure months. CONCLUSIONS: These findings, although weak, lend support to the claim that in utero exposure to influenza epidemics is a risk factor for adult schizophrenia. [Abstract]

Takei N, Sham P, O'Callaghan E, Murray GK, Glover G, Murray RM
Prenatal exposure to influenza and the development of schizophrenia: is the effect confined to females?
Am J Psychiatry. 1994 Jan;151(1):117-9.
The question of whether prenatal exposure to influenza epidemics is associated with an increased risk of later schizophrenia remains controversial. The authors examined this relationship, using data on the dates of birth and gender of 3,827 schizophrenic patients born in England and Wales between 1938 and 1965 and first admitted to hospitals in the 1980s, the numbers of live births between 1938 and 1965, and the numbers of deaths attributed to influenza between 1937 and 1965. The analysis showed that females, but not males, exposed to influenza epidemics 5 months before birth had a significantly greater rate of adult schizophrenia. [Abstract]

Morgan V, Castle D, Page A, Fazio S, Gurrin L, Burton P, Montgomery P, Jablensky A
Influenza epidemics and incidence of schizophrenia, affective disorders and mental retardation in Western Australia: no evidence of a major effect.
Schizophr Res. 1997 Jul 25;26(1):25-39.
In-utero exposure to influenza has been implicated as a risk factor for developmental CNS damage. This study tests the hypothesis that in-utero exposure to influenza: (1) in the second gestational trimester is associated with an increased risk of schizophrenia and affective psychoses; and (2) in the first gestational trimester is associated with an increased risk of mental retardation. Analysis was confined to 1852 cases on the Western Australian psychiatric case register with ICD-9 diagnoses of schizophrenia, affective psychoses, or neurotic depression (comparison group), and 804 cases on the Intellectual Handicap Register with mental retardation that were related to 82,963 'exposed' and 32,462 'non-exposed' births between 1950 and 1960 in the total population of Western Australia. The data were examined for effects associated with six influenza epidemics in the period 1950-1960. Using relative risk ratios for individual epidemics as well as Poisson regression and a proportional hazards model to examine systematic effects for the whole period, no major effect could be identified for maternal influenza on the incidence of schizophrenia, affective psychoses and neurotic depression, despite sufficient statistical power to detect an effect. However, a possible effect was found for mental retardation in males exposed in the first and second gestational trimester. [Abstract]

Kunugi H, Nanko S, Takei N, Saito K, Hayashi N, Kikumoto K, Hirai T, Kazamatsuri H
[Schizophrenia following prenatal exposure to influenza during second trimester]
Seishin Shinkeigaku Zasshi. 1993;95(6):453-62.
Mednick et al and O'Callaghan et al have recently reported that individuals exposed to the 1957 A2 influenza pandemic during their second trimester in utero are at risk for later schizophrenia. In this study, we determined whether their findings could be reproducible in a Japanese sample. In Japan, there were two waves of the 1957 A2 influenza pandemic; the first occurred from June to July, and the second from November to December. In addition, an epidemic of influenza A/B mixed type prevailed from January to February 1957. We obtained information on all dates of birth of 1187 individuals born between June 1955 and May 1960, who were treated for schizophrenia during the study period. November 1991 to September 1992, at 18 mental hospitals around Tokyo metropolitan areas. Hospital clinical diagnosis was used. We defined the index year from June 1957, beginning the first wave of the pandemic, to May 1958. We compared the number of schizophrenic births in each month of the index year with the average number of births in the corresponding month of the two years before, and following, the index year. The observed number of births in June 1957 and April 1958 were found to be significantly high compared with the average number of births for the corresponding month in the four control years. The 63% excess of schizophrenic births in June 1957 ensued about 5 months after the peak of influenza A/B mixed type epidemic; there was also 49% increase in births about 5 months after the second wave of the pandemic. Given that full term delivery occurred in our sample (ie, 9 months pregnancy), our results support the view of Mednick et al and O'Callaghan et al that maternal exposure to influenza in the mid-pregnancy increases the risk of developing schizophrenia. [Abstract]

O'Callaghan E, Sham P, Takei N, Glover G, Murray RM
Schizophrenia after prenatal exposure to 1957 A2 influenza epidemic.
Lancet. 1991 May 25;337(8752):1248-50.
The birth dates of schizophrenic inpatients in eight health regions in England and Wales were reviewed for any effect of the 1957 A2 influenza epidemic. 5 months after the peak infection prevalence, the number of births of individuals who later developed schizophrenia was 88% higher than the average number of such births in the corresponding periods of the 2 previous and the next 2 years. This finding is in accordance with a study from Helsinki and with clinical and neuropathological evidence of aberrant fetal brain development in the pathogenesis of schizophrenia. [Abstract]

Takei N, Van Os J, Murray RM
Maternal exposure to influenza and risk of schizophrenia: a 22 year study from The Netherlands.
J Psychiatr Res. 1995 Nov-Dec;29(6):435-45.
We investigated any effect of prenatal exposure to influenza during gestation on subsequent risk of schizophrenia using a national sample from The Netherlands. Dates of births of all Dutch-born schizophrenia (ICD-9) patients (n = 10,630) admitted to hospitals for the first time between 1970 and 1992 were examined in relation to the occurrence of influenza epidemics between 1947 and 1969. As a measure of prevalence of influenza, the number of deaths from influenza per month in The Netherlands was used. A Poisson regression analysis revealed that an increase in the prevalence of influenza 3 months prior to birth was followed by an increase in births of preschizophrenics, although this fell outside statistical significance (p = .11). However, the effect became marked in typical schizophrenics (n = 4726), but not in less typical cases (n = 5389). For typical schizophrenics, the parameter estimate derived from the regression model indicates that there was a 10% increase (95% confidence interval: -1 to 22%) in preschizophrenic births for every 500 deaths from influenza 3 months before birth. [Abstract]

Susser E, Lin SP, Brown AS, Lumey LH, Erlenmeyer-Kimling L
No relation between risk of schizophrenia and prenatal exposure to influenza in Holland.
Am J Psychiatry. 1994 Jun;151(6):922-4.
The authors compared the risk of schizophrenia in Dutch birth cohorts that were or were not exposed during the second trimester of gestation to the 1957 A2 influenza epidemic. Exposed birth cohorts did not have a higher risk of schizophrenia. These findings suggest that, in some populations, there is no relation between prenatal exposure to influenza and risk of schizophrenia. [Abstract]

Selten JP, Slaets JP
Evidence against maternal influenza as a risk factor for schizophrenia.
Br J Psychiatry. 1994 May;164(5):674-6.
We tested the hypothesis that second-trimester exposure to influenza is a risk factor for schizophrenia in the child. The dates of birth of Dutch schizophrenic in-patients were examined for any effect of the 1957 A2 influenza epidemic. Individuals who were in their second trimester of foetal life at the peak of the epidemic were at no greater risk of developing schizophrenia than controls. As the present study has a larger sample size than all previous European studies, and is supported by a large study in the USA, it provides strong evidence against the hypothesis that second-trimester exposure to influenza is a risk factor for schizophrenia. [Abstract]

Selten JP, Slaets J, Kahn R
Prenatal exposure to influenza and schizophrenia in Surinamese and Dutch Antillean immigrants to The Netherlands.
Schizophr Res. 1998 Feb 27;30(1):101-3.
There is evidence of an increased incidence of schizophrenia in Afro-Caribbean immigrants to the UK and in Surinamese- and Dutch Antillean immigrants to The Netherlands. We tested the hypothesis that second-trimester exposure to the 1957 A2 influenza pandemic, which swept through the Caribbean in the same period as it affected Western Europe, contributes to this phenomenon. The dates of birth of immigrants, discharged from a Dutch psychiatric institute with a diagnosis of schizophrenia, were examined for any effect of the pandemic. Individuals who were in their second-trimester of fetal life at the peak of the pandemic were at no greater risk of developing schizophrenia than controls. [Abstract]

Selten JP, Brown AS, Moons KG, Slaets JP, Susser ES, Kahn RS
Prenatal exposure to the 1957 influenza pandemic and non-affective psychosis in The Netherlands.
Schizophr Res. 1999 Aug 17;38(2-3):85-91.
Second-trimester exposure to the 1957 A2 influenza pandemic is a controversial risk factor for schizophrenia. Two earlier studies of the Dutch psychiatric registry failed to find an increased risk for exposed subjects, but diagnostic misclassification within the spectrum of non-affective psychoses has not yet been ruled out as an explanation for the negative findings. Using an enlarged data-set we examined not only whether second-trimester exposure to the epidemic is associated with an increased risk of schizophrenia (ICD:295), but also whether it is associated with an increased risk of paranoid states (ICD:297) or other non-organic psychoses (ICD:298). In this retrospective cohort study the risks of the above-mentioned disorders were compared for those exposed and unexposed to A2 influenza during the second trimester of fetal life. The risks for the exposed subjects were not significantly higher than the risks for the unexposed. The power of the study to detect a significant increase in the risk of schizophrenia was sufficient. If the relative risk of a lifetime hospitalization for schizophrenia for second-trimester exposed subjects (born January-April 1958) is assumed to be 1.3, the power of the study would be 0.97 (alpha=0.05; one-tailed testing). If the relative risk for subjects born five months after the peak of the epidemic (mid-February to mid-March 1958) is assumed to be 1.88, as reported for England and Wales, the power of the study would be close to 1.00. This was the largest study of its kind in Europe: 275 subjects were born in the period January-April 1958 and had a lifetime hospitalization for schizophrenia. This study indicates that there is no relation between second-trimester exposure to the 1957 influenza pandemic and risk of non-affective psychosis in the Dutch population. It adds to a growing body of work which does not support an association between maternal influenza and schizophrenia. [Abstract]

Grech A, Takei N, Murray RM
Maternal exposure to influenza and paranoid schizophrenia.
Schizophr Res. 1997 Aug 29;26(2-3):121-5.
Previous research has suggested that schizophrenics exposed to influenza in the second trimester have more delusions of jealousy, delusions of reference and suspiciousness. We therefore hypothesised that the risk-increasing effect of in utero exposure to influenza would be particularly demonstrable in paranoid schizophrenia. We studied patients with an ICD diagnosis of schizophrenia in England and Wales who were born each month between 1923 and 1965 (N = 17,247. Chi-square test for trend showed that an increase in influenza exposure level during the fifth month of gestation was accompanied by an increase in the proportion of patients with paranoid schizophrenia. However, logistic regression analysis including sex, seasonality and birth period in the model resulted in the loss of any significant association between in utero exposure to influenza and the development of paranoid schizophrenia, the loss of this significance being mainly accounted for by birth period. Therefore, the association in utero exposure to influenza and subsequent development of paranoid schizophrenia we hypothesised was not supported by our data. [Abstract]

Battle YL, Martin BC, Dorfman JH, Miller LS
Seasonality and infectious disease in schizophrenia: the birth hypothesis revisited.
J Psychiatr Res. 1999 Nov-Dec;33(6):501-9.
Research literature supports the notion that more people diagnosed with schizophrenia are born during the winter months than other seasons [O'Hare A, Walsh D, Torrey F. Seasonality of schizophrenia births in Ireland. Br J Psychiatry 1980;137:74 7; Pulver AE, Stewart W, Carpenter WT, Jr., Childs B. Risk factors in schizophrenia: season of birth in Maryland, USA. Br J Psychiatry 1983;143:389-96.]. Researchers have postulated that this surge in winter-birth schizophrenia may be related to increases in viral infectious such as influenza and measles [Watson CG, Kucala T, Tilleskjor C, Jacobs L. Schizophrenic birth seasonality in relation to incidence of infectious diseases and temperature extremes. Arch Gen Psychiatry 1984:41:85-90; Mednick SA, Machon RA, Huttunen MO, Bonnett D. Adult schizophrenia following prenatal exposure to an influenza epidemic. Arch Gen Psychiatry 1988;45:189-92.]. However, data supporting significant relationships between infectious disease and schizophrenia incidence has been equivocal [Kendell R, Kemp I. Maternal influenza in the etiology of schizophrenia. Arch Gen Psychiatry 1989;46:878-82; McGrath J, Castle D. Does influenza cause schizophrenia? A five year review. Aust N Z J Psychiatry 1995;29:23-31.]. The purpose of this study was to replicate and expand previous studies by examining seasonal and infectious disease influences on schizophrenia prevalence. It was hypothesized that: (1) there would be an increase in schizophrenia prevalence during the winter months; and (2) that a significant amount of variability in schizophrenia birthrates would be accounted for by rates of influenza and measles. A Georgia Medicaid database (N = 746,615) and statewide infectious disease tables were used to identify correlations. Medicaid recipients were divided into schizophrenia (n = 11,736) and non-schizophrenia (n = 734,879) groups. A ratio of schizophrenic recipients to non-schizophrenic recipients was calculated for each birth cohort represented by each month of the year from 1948-1965. Multiple regression analyses indicated a significant relationship between winter season and schizophrenia incidence. However, neither influenza nor measles was predictive of schizophrenia prevalence. These findings were made using one of the largest sample of schizophrenic individuals in the literature to date. Limitations of the study are discussed, including the use of seasonal and prevalence correlations without data on patient linked maternal infections. [Abstract]

Torrey EF, Miller J, Rawlings R, Yolken RH
Seasonality of births in schizophrenia and bipolar disorder: a review of the literature.
Schizophr Res. 1997 Nov 7;28(1):1-38.
More than 250 studies, covering 29 Northern and five Southern Hemisphere countries, have been published on the birth seasonality of individuals who develop schizophrenia and/or bipolar disorder. Despite methodological problems, the studies are remarkably consistent in showing a 5-8% winter-spring excess of births for both schizophrenia and mania/bipolar disorder. This seasonal birth excess is also found in schizoaffective disorder (December-March), major depression (March-May), and autism (March) but not in other psychiatric conditions with the possible exceptions of eating disorders and antisocial personality disorder. The seasonal birth pattern also may shift over time. Attempts to correlate the seasonal birth excess with specific features of schizophrenia suggest that winter-spring births are probably related to urban births and to a negative family history. Possible correlations include lesser severity of illness and neurophysiological measures. There appears to be no correlation with gender, social class, race, measurable pregnancy and birth complications, clinical subtypes, or neurological, neuropsychological, or neuroimaging measures. Virtually no correlation studies have been done for bipolar disorder. Regarding the cause of the birth seasonality, statistical artifact and parental procreational habits are unlikely explanations. Seasonal effects of genes, subtle pregnancy and birth complications, light and internal chemistry, toxins, nutrition, temperature/weather, and infectious agents or a combination of these are all viable possibilities. [Abstract]

Chabot B, Germain-Robin S, Petit M, Dollfus S
[Early familial and environmental processes in schizophrenia. Importance of premorbid personality evaluation]
Encephale. 1998 Jul-Aug;24(4):309-14.
According to the neurodevelopmental hypothesis, antenatal aggressions (hypoxia and seasonal viral infections) could increase the risk of schizophrenia in adulthood as shown by an excess of obstetric complications and births in winter--spring in schizophrenic patients. As schizoid and schizotypal personality disorders are genetically linked to schizophrenia, we wanted to verify whether such disorders in the premorbid period in schizophrenic patients could be markers of a more genetic and less environmental sub-type of schizophrenia. Therefore, the aim of this study was to assess schizoid and schizotypal premorbid personality disorders (PPD) in 60 schizophrenic patients, and to assess the weight of familial and environmental factors according to the diagnosis of PPD. 41.7% of patients (25/60) had a schizoid or schizotypal PPD. Compared with patients without PPD, patients with PPD had more often schizophrenia spectrum disorders in first degree relatives (33.3% vs 14.7%, NS), less often obstetric complications (20.8% vs 50.0%, p < 0.05) and were less often born in the first half-year (44.0% vs 68.6%, p = 0.05). So, we showed a non significant positive association between schizoid--schizotypal PPD and family history of schizophrenia spectrum disorders, and a significant negative association between PPD and environmental factors: obstetric complications (OC) and birth in winter-spring. So, the absence of PPD could enable us to identify a sub-group of patients in whom environmental factors play a major role. Moreover, the relations between genetic factors and PPD seem to be complicated. Nevertheless, the notion of PPD could give information about the kind of genetic factors implicated in schizophrenia. [Abstract]

Beraki S, Aronsson F, Karlsson H, Ogren SO, Kristensson K
Influenza A virus infection causes alterations in expression of synaptic regulatory genes combined with changes in cognitive and emotional behaviors in mice.
Mol Psychiatry. 2005 Mar;10(3):299-308.
Epidemiological studies have indicated a link between certain neuropsychiatric diseases and exposure to viral infections. In order to examine long-term effects on behavior and gene expression in the brain of one candidate virus, we have used a model involving olfactory bulb injection of the neuro-adapted influenza A virus strain, WSN/33, in C57Bl/6 mice. Following this olfactory route of invasion, the virus targets neurons in the medial habenular, midline thalamic and hypothalamic nuclei as well as monoaminergic neurons in the brainstem. The mice survive and the viral infection is cleared from the brain within 12 days. When tested 14-20 weeks after infection, the mice displayed decreased anxiety in the elevated plus-maze and impaired spatial learning in the Morris water maze test. Elevated transcriptional activity of two genes encoding synaptic regulatory proteins, regulator of G-protein signaling 4 and calcium/calmodulin-dependent protein kinase IIalpha, was found in the amygdala, hypothalamus and cerebellum. It is of particular interest that the gene encoding RGS4, which has been related to schizophrenia, showed the most pronounced alteration. This study indicates that a transient influenza virus infection can cause persistent changes in emotional and cognitive functions as well as alterations in the expression of genes involved in the regulation of synaptic activities.