autoimmunity and infection in schizophrenia



(Updated 6/14/05)

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. [Abstract]

Fatemi SH, Earle J, Kanodia R, Kist D, Emamian ES, Patterson PH, Shi L, Sidwell R
Prenatal viral infection leads to pyramidal cell atrophy and macrocephaly in adulthood: implications for genesis of autism and schizophrenia.
Cell Mol Neurobiol. 2002 Feb;22(1):25-33.
We investigated the role of maternal exposure to human influenza virus (H1N1) in C57BL/6 mice on Day 9 of pregnancy on pyramidal and nonpyramidal cell density, pyramidal nuclear area, and overall brain size in Day 0 neonates and 14-week-old progeny and compared them to sham-infected cohorts. Pyramidal cell density increased significantly (p < 0.0038) by 170% in Day 0 infected mice vs. controls. Nonpyramidal cell density decreased by 33% in Day 0 infected progeny vs. controls albeit, nonsignificantly. Pyramidal cell nuclear size decreased significantly (p < 0.0465) by 29% in exposed newborn mice vs. controls. Fourteen-week-old exposed mice continued to show significant increases in both pyramidal and nonpyramidal cell density values vs. controls respectively (p < 0.0085 E1 (exposed group 1), p < 0.0279 E2 (exposed group 2) pyramidal cell density; p < 0.0092 E1, p < 0.0252 E2, nonpyramidal cell density). By the same token, pyramidal cell nuclear size exhibited 37-43% reductions when compared to control values; these were statistically significant vs. controls (p < 0.04 E1, p < 0.0259 E2). Brain and ventricular area measurements in adult exposed mice also showed significant increases and decreases respectively vs. controls. Ventricular brain ratios exhibited 38-50% decreases in exposed mice vs. controls. While the rate of pyramidal cell proliferation per unit area decreased from birth to adulthood in both control and exposed groups, nonpyramidal cell growth rate increased only in the exposed adult mice. These data show for the first time that prenatal exposure of pregnant mice on Day 9 of pregnancy to a sublethal intranasal administration of influenza virus has both short-term and long-lasting deleterious effects on developing brain structure in the progeny as evident by altered pyramidal and nonpyramidal cell density values; atrophy of pyramidal cells despite normal cell proliferation rate and final enlargement of brain. Moreover, abnormal corticogenesis is associated with development of abnormal behavior in the exposed adult mice. [Abstract]

O'Callaghan E, Sham PC, Takei N, Murray G, Glover G, Hare EH, Murray RM
The relationship of schizophrenic births to 16 infectious diseases.
Br J Psychiatry. 1994 Sep;165(3):353-6.
BACKGROUND. 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. METHOD. 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. RESULTS. 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. CONCLUSIONS. 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. [Abstract]

Brown AS, Schaefer CA, Wyatt RJ, Goetz R, Begg MD, Gorman JM, Susser ES
Maternal exposure to respiratory infections and adult schizophrenia spectrum disorders: a prospective birth cohort study.
Schizophr Bull. 2000;26(2):287-95.
We sought to examine the relationship between maternal exposure to adult respiratory infections and schizophrenia spectrum disorder (SSD) in the Prenatal Determinants of Schizophrenia (PDS) Study, a large birth cohort investigation. Previous work suggests that second trimester exposure to respiratory infection may be a risk factor for SSD. We therefore examined whether this class of infection was associated with adult SSD. For this purpose, we capitalized on several design advantages of the PDS Study, including a comprehensive, prospective data base on physician-diagnosed infections and a continuous followup in which diagnoses of SSD were made, in the majority, by face-to-face interview. Second trimester exposure to respiratory infections was associated with a significantly increased risk of SSD, adjusting for maternal smoking, education, and race (rate ratio [RR] = 2.13 [1.05-4.35], chi2 = 4.36, df= 1,p = 0.04); no associations were shown for first trimester and third trimester exposure to these respiratory infections. These findings support-and extend-previous studies suggesting that second trimester respiratory infections are risk factors for SSD. This study therefore has implications toward uncovering the etiology of schizophrenia and developing preventive strategies. [Abstract]

Shi L, Fatemi SH, Sidwell RW, Patterson PH
Maternal influenza infection causes marked behavioral and pharmacological changes in the offspring.
J Neurosci. 2003 Jan 1;23(1):297-302.
Maternal viral infection is known to increase the risk for schizophrenia and autism in the offspring. Using this observation in an animal model, we find that respiratory infection of pregnant mice (both BALB/c and C57BL/6 strains) with the human influenza virus yields offspring that display highly abnormal behavioral responses as adults. As in schizophrenia and autism, these offspring display deficits in prepulse inhibition (PPI) in the acoustic startle response. Compared with control mice, the infected mice also display striking responses to the acute administration of antipsychotic (clozapine and chlorpromazine) and psychomimetic (ketamine) drugs. Moreover, these mice are deficient in exploratory behavior in both open-field and novel-object tests, and they are deficient in social interaction. At least some of these behavioral changes likely are attributable to the maternal immune response itself. That is, maternal injection of the synthetic double-stranded RNA polyinosinic-polycytidylic acid causes a PPI deficit in the offspring in the absence of virus. Therefore, maternal viral infection has a profound effect on the behavior of adult offspring, probably via an effect of the maternal immune response on the fetus. [Abstract]

Fatemi SH, Emamian ES, Kist D, Sidwell RW, Nakajima K, Akhter P, Shier A, Sheikh S, Bailey K
Defective corticogenesis and reduction in Reelin immunoreactivity in cortex and hippocampus of prenatally infected neonatal mice.
Mol Psychiatry. 1999 Mar;4(2):145-54.
Recent reports indicate an association between second trimester human influenza viral infection and later development of schizophrenia. Postmortem human brain studies also provide evidence for reduction in Reelin mRNA (an important secretory protein responsible for normal lamination of the brain) in schizophrenic brains. We hypothesized that human influenza infection in day 9 pregnant mice would alter the expression of reelin in day 0 neonatal brains. Prenatally-infected murine brains from postnatal day 0 showed significant reductions in reelin-positive cell counts in layer I of neocortex and other cortical and hippocampal layers when compared to controls. Whereas layer I Cajal-Retzius cells produced significantly less Reelin in infected animals, the same cells showed normal production of calretinin and nNOS when compared to control brains. Moreover, prenatal viral infection caused decreases in neocortical and hippocampal thickness. These results implicate a potential role of prenatal viral infection in causation of neuronal migration abnormalities via reduction in Reelin production in neonatal brains. [Abstract]

Zuckerman L, Weiner I
Maternal immune activation leads to behavioral and pharmacological changes in the adult offspring.
J Psychiatr Res. 2005 May;39(3):311-23.
Maternal exposure to viral infection has been associated with an increased risk of schizophrenia in the offspring, and it has been suggested that the maternal immune response may interfere with normal fetal brain development. Although studies in rodents have shown that perinatal viral infections can lead to neuropathological and behavioral abnormalities considered relevant to schizophrenia, it is not clear whether these consequences are due to the infection itself or to the maternal immune response to infection. We show that an induction of maternal immune stimulation without exposure to a virus by injecting pregnant dams with the synthetic cytokine releaser polyriboinosinic-polyribocytidilic acid (poly I:C) leads to abnormal behavioral and pharmacological responses in the adult offspring. As in schizophrenia, these offspring displayed excessive behavioral switching, manifested in the loss of latent inhibition and in rapid reversal learning. Consistent with the clinical pharmacology of schizophrenia, both deficits were alleviated by antipsychotic treatment. In addition, these offspring displayed increased sensitivity to the locomotor-stimulating effects of MK-801, pointing to developmental alterations of the dopaminergic and/or glutamatergic systems. Prenatal poly I:C administration did not produce learning deficits in classical fear conditioning, active avoidance, discrimination learning and water maze. These results show that the maternal immune response is sufficient to cause behavioral and pharmacological alterations relevant to schizophrenia in the adult offspring. [Abstract]

Fatemi SH, Pearce DA, Brooks AI, Sidwell RW
Prenatal viral infection in mouse causes differential expression of genes in brains of mouse progeny: A potential animal model for schizophrenia and autism.
Synapse. 2005 Aug;57(2):91-9.
Schizophrenia and autism are neurodevelopmental disorders with genetic and environmental etiologies. Prenatal viral infection has been associated with both disorders. We investigated the effects of prenatal viral infection on gene regulation in offspring of Balb-c mice using microarray technology. The results showed significant upregulation of 21 genes and downregulation of 18 genes in the affected neonatal brain homogenates spanning gene families affecting cell structure and function, namely, cytosolic chaperone system, HSC70, Bicaudal D, aquaporin 4, carbonic anhydrase 3, glycine receptor, norepinephrine transporter, and myelin basic protein. We also verified the results using QPCR measurements of selected mRNA species. These results show for the first time that prenatal human influenza viral infection on day 9 of pregnancy leads to alterations in a subset of genes in brains of exposed offspring, potentially leading to permanent changes in brain structure and function. [Abstract]

Cazzullo CL, Saresella M, Roda K, Calvo MG, Bertrando P, Doria S, Clerici M, Salvaggio A, Ferrante P
Increased levels of CD8+ and CD4+ 45RA+ lymphocytes in schizophrenic patients.
Schizophr Res. 1998 May 4;31(1):49-55.
Peripheral blood (PB) lymphocyte subpopulations, IgG, IgM, IgA and IgE serum immunoglobulins and C3 and C4 complement fractions were evaluated in 29 schizophrenic patients, 31 of their relatives and 20 healthy subjects. The patients fulfilled DSM-III criteria for schizophrenia, and were unmedicated for 3 months prior to the PB sample collection. When compared to healthy controls and their own relatives, the schizophrenic patients showed a lower level of CD4+ cells, while the CD4+ 45RA+ (naive) subset was significantly higher. Conversely, the number of CD4+ 45RA- (memory) lymphocytes was significantly lower in schizophrenic patients in comparison to their relatives and controls, while the CD8+ supressor/cytotoxic T-cell percentage was significantly higher. No significant differences were observed for the IgG, IgM, IgA, IgE and C3 and C4 complement fraction levels among the three groups. The present data confirm the presence of immunological abnormalities in schizophrenic patients and suggest a possible role of environmental factors in the triggering of an autoimmune pathogenic mechanism. [Abstract]

Sirota P, Firer MA, Schild K, Tanay A, Elizur A, Meytes D, Slor H
Autoantibodies to DNA in multicase families with schizophrenia.
Biol Psychiatry. 1993 Mar 15;33(6):450-5.
In an attempt to define the autoimmune status of members of multicase families with schizophrenia, sera of both patients and healthy relatives from 28 such cases were tested for antinuclear antibodies, anti-double-stranded DNA, and anti-single-stranded DNA autoantibodies. These autoantibodies were significantly more frequent in both schizophrenic patients and healthy relatives than in normal subjects. Immunoglobulin (Ig) M anti-DNA antibodies were more common in patients, whereas in healthy relatives, IgG anti-DNA antibodies were more common. No significant differences were found between schizophrenic patients and their healthy relatives. The data indicate that an autoimmune process may be involved in the etiology of a subset of patients with schizophrenia. [Abstract]

Schattner A, Cori Y, Hahn T, Sirota P
No evidence for autoimmunity in schizophrenia.
J Autoimmun. 1996 Oct;9(5):661-6.
We studied parameters of cellular immunity in 23 schizophrenic patients and compared them to 16 matched healthy controls and to 12 patients with rheumatoid arthritis (RA). None of the patients was receiving neuroleptic drug treatment before the study. We used highly sensitive methods to examine the interferon system by determination of the interferon-induced enzyme 2'-5' oligo-adenylate synthetase [2-5A] in peripheral blood mononuclear cells. Tumor necrosis factor alpha (TNF-alpha) production was measured in the plasma and in vitro by bioassay of supernatants of stimulated blood cells and of unstimulated cells (spontaneous TNF secretion). In addition, we determined cell-mediated (spontaneous) cytotoxicity, major T cell subsets (CD3, CD4 and CD8 positive cells) and serum neopterin levels. No statistically significant differences could be found between the patients with schizophrenia and the control group in any of the tests used, and no particular subgroup of patients could be identified. In contrast, RA patients had increased serum neopterin and TNF levels, increased LPS-induced TNF production in vitro, increased 2-5A levels and a decrease in CD8 cells associated with an increase in CD4 cells. Thus, in the group of patients studied, we could find no substantiation for the presence of either autoimmune or occult viral cofactors in the pathogenesis of schizophrenia. [Abstract]

Haack M, Hinze-Selch D, Fenzel T, Kraus T, Kühn M, Schuld A, Pollmächer T
Plasma levels of cytokines and soluble cytokine receptors in psychiatric patients upon hospital admission: effects of confounding factors and diagnosis.
J Psychiatr Res. 1999 Sep-Oct;33(5):407-18.
It has been hypothesized that the immune system plays a pathogenetic role in psychiatric disorders, in particular in major depression and schizophrenia. This hypothesis is supported by a number of reports on altered circulating levels and in vitro production of cytokines in these disorders. However, the respective evidence is not consistent. This may be in part due to an incomplete control for numerous confounding influences in earlier studies. We investigated the plasma levels of cytokines and soluble cytokine receptors in psychiatric patients (N = 361) upon hospital admission and compared the results to those obtained in healthy controls (N = 64). By multiple regression analysis we found that circulating levels of interleukin-1 receptor antagonist (IL-1Ra), soluble IL-2 receptor (sIL-2R), tumor necrosis factor-alpha (TNF-alpha), soluble TNF receptors (sTNF-R p55, sTNF-R p75) and IL-6 were significantly affected by age, the body mass index (BMI), gender, smoking habits, ongoing or recent infectious diseases, or prior medication. Cytokine or cytokine receptor levels were significantly increased in patients treated with clozapine (sIL-2R, sTNF-R p75), lithium (TNF-alpha, sTNF-R p75, IL-6) or benzodiazepines (TNF-alpha, sTNF-R p75). Taking all these confounding factors into account, we found no evidence for disease-related alterations in the levels of IL-1Ra, sIL-2R, sTNF-R p75 and IL-6, whereas levels of TNF-alpha and sTNF-R p55 in major depression and sTNF-R p55 in schizophrenia were slightly decreased compared to healthy controls. We conclude that, if confounding factors are carefully taken into account, plasma levels of the above mentioned cytokines and cytokine receptors yield little, if any, evidence for immunopathology in schizophrenia or major depression. [Abstract]

Brown AS, Hooton J, Schaefer CA, Zhang H, Petkova E, Babulas V, Perrin M, Gorman JM, Susser ES
Elevated maternal interleukin-8 levels and risk of schizophrenia in adult offspring.
Am J Psychiatry. 2004 May;161(5):889-95.
OBJECTIVE: Many studies have implicated prenatal infection in the etiology of schizophrenia. Cytokines, a family of soluble polypeptides, are critically important in the immune response to infection and in other inflammatory processes. The goal of this study was to determine whether second-trimester levels of four cytokines-interleukin-8 (IL-8), interleukin-1beta (IL-1beta), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-alpha)-are higher in the mothers of offspring who later developed schizophrenia spectrum disorders than in matched comparison subjects. METHOD: The authors conducted a nested case-control study of maternal serum cytokine levels in a large birth cohort, born 1959-1967. Cases (N=59) were subjects diagnosed with schizophrenia spectrum disorders (mostly schizophrenia and schizoaffective disorder) who had available second-trimester maternal serum samples. Comparison subjects (N=105) were members of the birth cohort, had not been diagnosed with a schizophrenia spectrum disorder or major affective disorder, and were matched to subjects with schizophrenia for date of birth, gender, length of time in the cohort, and availability of maternal sera. Maternal second-trimester serum levels of IL-8, IL-1beta, IL-6, and TNF-alpha were determined by sandwich enzyme-linked immunosorbent assay. RESULTS: The second-trimester IL-8 levels in mothers of offspring with schizophrenia spectrum disorders were significantly higher than those of the mothers of comparison subjects. There were no differences between subjects with schizophrenia and comparison subjects with respect to maternal levels of IL-1beta, IL-6, or TNF-alpha. CONCLUSIONS: Using prospectively collected prenatal sera in a large and well-characterized birth cohort, the authors have documented a significant association between maternal IL-8 level during the second trimester and risk of schizophrenia spectrum disorders in the offspring. These findings provide further support for a substantive role of in utero infection or inflammation in the etiology of schizophrenia. Moreover, these results may have important implications for elucidating the mechanisms by which disrupted fetal development raises the risk of this disorder. [Abstract]

Buka SL, Tsuang MT, Torrey EF, Klebanoff MA, Wagner RL, Yolken RH
Maternal cytokine levels during pregnancy and adult psychosis.
Brain Behav Immun. 2001 Dec;15(4):411-20.
We investigated levels of maternal cytokines in late pregnancy in relation to the subsequent development of adult schizophrenia and other psychoses in their offspring. The sample included the mothers of 27 adults with schizophrenia and other psychotic illnesses and 50 matched unaffected controls from the Providence cohort of the Collaborative Perinatal Project. Serum samples were analyzed for interleukin 1 beta (IL-1-beta), interleukin 2 (IL-2), interleukin 6 (IL-6), interleukin 8 (IL-8), and tumor necrosis factor alpha (TNF-alpha) by enzyme immunoassay. Maternal levels of TNF-alpha were significantly elevated among the case series (t = 2.22, p =.04), with evidence of increasing odds of psychosis in relation to higher cytokine levels. We did not find significant differences between case and control mothers in the serum levels of IL-1, IL-2, IL-6, or IL-8. These data support previous clinical investigations reporting maternal infections during pregnancy as a potential risk factor for psychotic illness among offspring. [Abstract]

van Kammen DP CG, Kelley ME, Gurklis JA, Yao JK
Elevated interleukin-6 in schizophrenia
Psychiatry Res. 1999 Oct 11;87(2-3):129-36.
Interleukin 6 (IL-6) levels have been shown to be increased in a number of autoimmune disorders and have recently been shown to be elevated in the serum of schizophrenic patients. Given the involvement of the CNS in schizophrenia, levels of interleukin-6 in the CSF are also of interest. Thus, we examined levels of both CSF and serum IL-6 concomitantly to determine if these levels were different from control values. In addition, we examined these measures in patients both on and off antipsychotic drugs to determine if any medication or exacerbation effects may account for the difference from controls. CSF IL-6 was measured by ELISA in 61 drug-free male schizophrenic (DSM-IIIR) patients and 25 well-screened healthy male control subjects. Serum IL-6 was measured in 43 of the 61 patients, and in 16 control subjects. Serum IL-6 was significantly higher in the schizophrenic patients compared to control subjects. CSF IL-6 was also higher in the patients, but the difference was not statistically significant. Paired data showed no medication or exacerbation effects on CSF IL-6, but plasma IL-6 significantly decreased in patients that experienced an exacerbation after medication withdrawal. The results indicate that IL-6 levels may be altered in schizophrenia. The relative decrease in exacerbated patients following haloperidol withdrawal may be indicative of a compensatory response of plasma IL-6 levels to relapse. [Abstract]

Naudin J, Mège JL, Azorin JM, Dassa D
Elevated circulating levels of IL-6 in schizophrenia.
Schizophr Res. 1996 Jul 5;20(3):269-73.
Schizophrenia may result from immune or inflammatory disorders, which are mediated by cytokines. Data in this field are heterogeneous and often contradictory. We investigated circulating levels of IL-6 and TNF-alpha, two distinct proinflammatory cytokines. Using immunoassay, we assessed IL-6 and TNF-alpha in serum from chronic schizophrenic patients (n = 30) and normal controls (n = 15). Circulating levels of IL-6 were higher in patients than in controls; those of TNF-alpha were not significantly higher than in controls. In addition, IL-6 levels were higher in patients with acute exacerbation of schizophrenia than in patients with remissions. Our results suggest that immunologic abnormalities in schizophrenia may be related to a specific inflammatory process mediated by IL-6. An interesting line of research would be the evaluation of IL-6 cerebral production in CSF. [Abstract]

Yang ZW, Chengappa KN, Shurin G, Brar JS, Rabin BS, Gubbi AV, Ganguli R
An association between anti-hippocampal antibody concentration and lymphocyte production of IL-2 in patients with schizophrenia.
Psychol Med. 1994 May;24(2):449-55.
Serum concentrations of anti-hippocampal antibodies and in vitro production of the lymphokine interleukin-2 (IL-2) in response to phytohaemagglutinin (PHA) stimulation were determined using an enzyme immunoassay in 49 schizophrenic patients and 41 healthy controls. Decrease in IL-2 production, a finding frequently associated with many autoimmune diseases, was associated with an elevation in anti-hippocampal antibody optical density (AHA-OD) in schizophrenic patients. Although some control subjects had elevated antibody levels, this elevation was not associated with decreased IL-2 production. Low IL-2 production is well known to be a state marker associated with active autoimmune disease. We suggest that production of hippocampal antibody is a trait marker of vulnerability to autoimmune diseases. Thus, our finding of low IL-2 production in patients with high concentrations of hippocampal antibody is compatible with the possibility that such patients have an ongoing autoimmune process. [Abstract]

Torrey EF
A viral-anatomical explantation of schizophrenia.
Schizophr Bull. 1991;17(1):15-8.
Recent neuropathological and neuroradiological studies of schizophrenia have pointed to the medial temporal cortex, especially the hippocampus, parahippocampal gyrus, and amygdala, as the areas primarily affected by this disease. Localization of the disease process to these structures may be explained anatomically because they are immediately contiguous to the foramen rotundum. Some viruses are known to ascend the trigeminal nerve and enter the cranial cavity through the foramen rotundum. They might latently infect the medial temporal cortex and be reactivated in early adulthood, producing the symptoms of schizophrenia. The distance from the nasal mucosa to the medial temporal cortex is less than 2 cm in infants. An anatomical explanation of schizophrenia could account for the seasonality of schizophrenic births, the observed excess birth trauma in schizophrenic individuals, the clinical aspects of schizophrenia, such as auditory hallucinations, and the genetic component of the disease. [Abstract]

Ganguli R, Brar JS, Solomon W, Chengappa KN, Rabin BS
Altered interleukin-2 production in schizophrenia: association between clinical state and autoantibody production.
Psychiatry Res. 1992 Nov;44(2):113-23.
Mitogen-stimulated interleukin-2 (IL-2) production was measured in 122 patients who met Research Diagnostic Criteria for schizophrenia and 98 normal control subjects. The presence of autoantibodies against seven common antigens was also determined. There was no relationship between the presence of circulating autoantibodies and IL-2 production in control subjects. In patients, however, autoantibody-positive, acutely ill patients had significantly lower IL-2 production as compared with other patients and control subjects. Never-medicated patients showed the same trends for decreased IL-2 production in association with autoantibodies. These data suggest that decreased IL-2 production is associated with acute illness in schizophrenic patients who produce autoantibodies, a trait known to be associated with increased vulnerability to autoimmune disease. [Abstract]

Arolt V, Rothermundt M, Wandinger KP, Kirchner H
Decreased in vitro production of interferon-gamma and interleukin-2 in whole blood of patients with schizophrenia during treatment.
Mol Psychiatry. 2000 Mar;5(2):150-8.
A pattern of aberrations in the T-cell cytokine system that is typical for autoimmune disorders has also been reported in patients with schizophrenia, namely a decreased interleukin-2 (IL-2) production and increased levels of the soluble IL-2 receptor (sIL-2R). It has also been reported that the production of interferon-gamma (IFN-gamma) may be lowered. In a longitudinal design, we studied the production of both IFN-gamma and IL-2 and their correlation in patients with schizophrenia during treatment and investigated whether associations exist between cytokine production and clinical variables. The production of IFN-gamma and IL-2 was measured in equal numbers (n = 29) of patients with schizophrenia (DSM-IV) and controls who were matched for age and gender. Patients were measured 1 day after admission (T1), after 14 (T2) and 28 (T2) days of treatment. Psychopathology was assessed after these times. The production of both IFN-gamma and IL-2 was significantly lower in patients than in controls throughout the whole investigation period (T1-T3). The productions of both cytokines were significantly correlated in controls (r = 0.60, P </= 0.001) as well as in patients with schizophrenia (mean production T1-T3: r = 0.71, P </= 0.001). No associations between cytokine measurements and psychopathology or age-at-onset could be found. Our findings of lowered and correlated IFN-gamma and IL-2 production indicate that alterations in the cytokine system of patients with schizophrenia might resemble those in autoimmune disorders. It is suggested that these immunological abnormalities are associated with acute exacerbation, rather than with a clinical subtype of schizophrenia. [Abstract]

Kim YK, Lee MS, Suh KY
Decreased interleukin-2 production in Korean schizophrenic patients.
Biol Psychiatry. 1998 May 1;43(9):701-4.
BACKGROUND: It has been postulated that autoimmune process may play a role in the pathogenesis of symptoms in some schizophrenic patients. Findings of altered interleukin (IL) regulation have been regarded as additional proof that schizophrenia has an autoimmunological background. METHODS: Sixteen patients who fulfilled DSM-IV criteria for schizophrenia and who were drug free for at least six months and the same number of age- and sex-matched controls were recruited. The severity of symptoms in schizophrenia was assessed by BPRS. Phytohemagglutinin (PHA)-stimulated production and serum level of IL-1 beta, IL-2, and IL-6 were measured by enzyme-linked immunosorbent assay (ELISA). RESULTS: There was a significant decrease of IL-2 production (p < .01) in schizophrenic patients and a significant increase of IL-2 serum level (p < .01). No significant difference of IL-1 beta and IL-6 was found. Some patients and controls had measurable serum level of IL-1 beta and IL-6. No significant correlation between production and serum level of IL-1 beta, -2, -6 and age, duration of illness, and BPRS score in schizophrenics was found. CONCLUSIONS: This is the first study to describe a decrease of IL-2 production and increase of IL-2 serum level in non-Caucasian schizophrenic patients. These findings are further evidence that autoimmune process is present, regardless of ethnic origin, in some schizophrenic patients. [Abstract]

Ganguli R, Brar JS, Chengappa KR, DeLeo M, Yang ZW, Shurin G, Rabin BS
Mitogen-stimulated interleukin-2 production in never-medicated, first-episode schizophrenic patients. The influence of age at onset and negative symptoms.
Arch Gen Psychiatry. 1995 Aug;52(8):668-72.
BACKGROUND: Decreased interleukin-2 (IL-2) production is characteristic of active autoimmune diseases and has previously been reported in patients with schizophrenia. We attempted to replicate this finding in never-medicated schizophrenic patients and examine the possible correlation between IL-2 production and clinical variables. METHODS: The production of IL-2 was measured in equal numbers (N = 33) of DSM-III-R-diagnosed schizophrenic patients and controls who were matched for age, race, and gender. Patients were also assessed for positive, negative, and depressive symptoms. RESULTS: The production of IL-2 was significantly lower in patients than in controls. There was a significant positive correlation between IL-2 production and age at onset, and significant negative correlation between IL-2 production and negative symptom scores. In multivariate analyses, the predictive power was stronger for age at onset than for negative symptoms. Positive or depressive symptoms were unrelated to IL-2 production. CONCLUSIONS: Our finding of low IL-2 production in neuroleptic-native schizophrenic patients confirms that this finding is not confounded by medications. The correlation of low IL-2 production with younger age at onset suggests that this may be a marker for a subtype of the illness or for severity. [Abstract]

Hornberg M, Arolt V, Wilke I, Kruse A, Kirchner H
Production of interferons and lymphokines in leukocyte cultures of patients with schizophrenia.
Schizophr Res. 1995 May;15(3):237-42.
Recently, several lines of evidence have suggested the possible of immunological dysfunction in the pathogenesis of schizophrenia. We therefore investigated the ability to produce interferons and lymphokines in response to mitogenic or viral stimulation in a whole blood assay of 37 schizophrenic patients (DSM-III-R) and of 42 healthy blood donors. Phytohaemagglutinin (PHA) was used for the induction of interleukin-2 (IL-2), interferon gamma (INF gamma), interleukin-6 (IL-6) and the soluble interleukin-2 receptor (sIL-2R) and Newcastle Disease Virus (NDV) for the induction of interferon alpha 2 (INF alpha 2). All lymphokines and, in addition, the sIL-2R in the sera were determined by ELISA technique. The psychopathological status of the patients was assessed by psychiatrists according to internationally accepted standards. The patient group showed a trend to lower levels of the interferons alpha 2 and gamma and a significant decrease of IL-2 production. The sIL-2R levels were significantly increased in the sera of schizophrenic patients. The latter increase was associated with a poor assessment of prognosis (Strauss and Carpenter). This association appears to be of interest. However, its significance is not understood, since longitudinal studies could not be performed. [Abstract]

Zhang XY, Zhou DF, Zhang PY, Wu GY, Cao LY, Shen YC
Elevated interleukin-2, interleukin-6 and interleukin-8 serum levels in neuroleptic-free schizophrenia: association with psychopathology.
Schizophr Res. 2002 Oct 1;57(2-3):247-58.
Cytokines have been one of the recent focal points of immunological research in schizophrenia. The present study was to assess the serum levels of some of interleukins in schizophrenia and their relationships with the psychopathological parameters. Seventy physically healthy Chinese patients, who met DSM-III-R criteria for schizophrenia and who were drug-free for at least 2 weeks, were compared with 30 age- and sex-matched Chinese normal controls. The psychopathology of schizophrenia was assessed by the Positive and Negative Syndrome Scale (PANSS). Serum levels of IL-6 and IL-8 were measured by sandwich enzyme-linked immunosorbent assay (ELISA), and serum IL-2 level was assayed by radioimmunometric assay (RIA). Serum levels of IL-2, IL-6 and IL-8 were significantly elevated in patients with a chronic form of schizophrenia (all p<0.05). There was a significant inverse relationship between IL-2 level and the PANSS positive subscale P (r=-0.31, p=0.006) and a significant positive correlation between IL-8 level and PANSS negative subscale N (r=0.25, p=0.036) in schizophrenic patients. In control subjects, a significant and positive relationship between serum IL-2 and IL-6 (r=0.513, p=0.004) was noted, whereas, there was a significant and negative relationship between IL-2 and IL-8 in schizophrenic patients (r=-0.28, p=0.02). Our data confirms and supports the view that immune disturbance is involved in schizophrenia, which is compatible with the possibility that Chinese schizophrenic patients have an ongoing autoimmune process. This immune disturbance is related to the subgroup of schizophrenic patients with characteristic clinical variables. The dysfunction of interaction or inter-adjustment between different cytokines may exist in schizophrenic patients. [Abstract]

Kaminska T, Wysocka A, Marmurowska-Michalowska H, Dubas-Slemp H, Kandefer-Szersze? M
Investigation of serum cytokine levels and cytokine production in whole blood cultures of paranoid schizophrenic patients.
Arch Immunol Ther Exp (Warsz). 2001;49(6):439-45.
There is some evidence that the pathophysiology of schizophrenia is related to changes in the innate and adaptive immune systems. In an attempt to define a potential immunological dysfunction in schizophrenia, we measured the serum levels of several cytokines in the sera of 24 patients with paranoid schizophrenia and investigated the cytokine production in whole blood assays after stimulation in vitro with virus (Newcastle disease), phytohemagglutinin (PHA) or bacterial lipopolysaccharide (LPS) and compared them with healthy, normal controls. A significant increase of interleukin 6 (IL-6), IL-8 and interferon gamma (IFN-gamma) levels, but a decreased L-10 level were observed in the sera of patients with schizophrenia. No significant changes in the serum levels of IL-2, IL-4, IFN-alpha and tumor necrosis factor alpha (TNF-alpha) were detected in these patients. When cytokine production in vitro was examined, a significant defect in PHA-induced IL-2, L-4 and IFN-gamma, and in virus-induced IFN-alpha production, but no significant alterations in LPS-induced IL-6, IL- 10 and TNF-alpha production were observed. In summary, increased serum levels of some cytokines such as IL-6, IL-8 and IFN-gamma indicate an activation of the inflammatory response in schizophrenia, while the in vitro assay indicates significant changes in the Th1 (decreased production of 1L-2 and IFN-gamma) and Th2 (decreased production of IL-4) cell system responses. The role of the defective EFN-alpha production in the regulation of the imbalance between Th1 and Th2 cell system responses is suggested. [Abstract]

Barak V, Barak Y, Levine J, Nisman B, Roisman I
Changes in interleukin-1 beta and soluble interleukin-2 receptor levels in CSF and serum of schizophrenic patients.
J Basic Clin Physiol Pharmacol. 1995;6(1):61-9.
Some evidence points towards a possible autoimmune role in the aetiology of schizophrenia. Experimental findings provide contradictory results regarding abnormalities in cytokine production in this disorder. In the present study we tested the production of cytokines in CSF and serum in 16 schizophrenic patients and 10 healthy controls (tumor necrosis factor alpha - TNF alpha; interleukins IL-1 beta, IL-2, IL-6, soluble IL-2 receptor). Cytokine levels were evaluated by radioactively-labeled antibodies (IL-1 beta, IL-2, IL-6), by enzyme-linked immunoassay (TNF) and by a sandwich enzyme immunoassay (soluble IL-2 receptor). No significant differences were found in either CSF fluid or serum levels of TNF and IL-2 or IL-6. Interleukin-1 beta was significantly decreased in patients' CSF and serum as compared to controls. Soluble interleukin-2 receptor levels were decreased in CSF of patients, but highly increased in their serum in comparison with controls. Changes in various cytokine levels in CSF fluid and serum of schizophrenic patients probably reflect interrelated process of growth, degeneration or neuroimmunological abnormalities, which may all play a role in the pathophysiology of schizophrenia. The present study supports evidence for change in immune activation, probably of peripheral origin, in schizophrenic patients. [Abstract]

Sirota P, Schild K, Elizur A, Djaldetti M, Fishman P
Increased interleukin-1 and interleukin-3 like activity in schizophrenic patients.
Prog Neuropsychopharmacol Biol Psychiatry. 1995 Jan;19(1):75-83.
1. The interleukins play an important role in the development and maintenance of the immune system 2. Decreased cell mediated immunity measures were found in schizophrenic patients. 3. The purpose of the present study was to study the spontaneous production of interleukin-1 (IL-1) and interleukin-3 like activity (IL-3-LA) by human mononuclear cells from schizophrenic patients in comparison to healthy individuals. 4. Interleukin-1 was increased significant by schizophrenic patients as compared to controls. 5. Interleukin-3 like activity was slightly elevated in schizophrenic patients as compared to controls. 6. These findings support the hypothesis of an autoimmune dysfunction in some schizophrenic patients. [Abstract]

Gilmore JH, Fredrik Jarskog L, Vadlamudi S, Lauder JM
Prenatal Infection and Risk for Schizophrenia: IL-1beta, IL-6, and TNFalpha Inhibit Cortical Neuron Dendrite Development.
Neuropsychopharmacology. 2004 Jul;29(7):1221-9.
Prenatal exposure to infection increases risk for schizophrenia, and we have hypothesized that inflammatory cytokines, generated in response to maternal infection, alter neuron development and increase risk for schizophrenia. We sought to study the effect of cytokines generated in response to infection-interleukin-1beta (IL-1beta), tumor necrosis factor-alpha (TNFalpha), and interleukin-6 (IL-6)-on the dendritic development of cortical neurons. Primary mixed neuronal cultures were obtained from E18 rats and exposed to 0, 100, or 1000 units (U)/ml of IL-1beta, TNFalpha, IL-6, or IL-1beta+TNFalpha for 44 h. MAP-2-positive neurons were randomly identified for each condition and the number of primary dendrites, nodes, and total dendrite length was determined. We found that 100 U of TNFalpha significantly reduced the number of nodes (27%, p=0.02) and total dendritic length (14%, p=0.04), but did not affect overall neuron survival. A measure of 100 U IL-1beta+TNFalpha significantly reduced the number of primary dendrites (17%, p=0.006), nodes (32%, p=0.001), and total dendritic length (30%, p<0.0001), although it did not affect overall neuron survival. At 1000 U, each cytokine significantly reduced the number of primary dendrites (14-24%), nodes (28-37%), as well as total dendritic length (25-30%); neuron survival was reduced by 14-21%. These results indicate that inflammatory cytokines can significantly reduce dendrite development and complexity of developing cortical neurons, consistent with the neuropathology of schizophrenia. These findings also support the hypothesis that cytokines play a key mechanistic role in the link between prenatal exposure to infection and risk for schizophrenia. [Abstract]

Torrey EF, Yolken RH
Toxoplasma gondii and schizophrenia.
Emerg Infect Dis. 2003 Nov;9(11):1375-80.
Recent epidemiologic studies indicate that infectious agents may contribute to some cases of schizophrenia. In animals, infections with Toxoplasma gondii can alter behavior and neurotransmitter function. In humans, acute infection with T. gondii can produce psychotic symptoms similar to those displayed by persons with schizophrenia. Since 1953, a total of 19 studies of T. gondii antibodies in persons with schizophrenia and other severe psychiatric disorders and in controls have been reported; 18 reported a higher percentage of antibodies in the affected persons; in 11 studies the difference was statistically significant. Two other studies found that exposure to cats in childhood was a risk factor for the development of schizophrenia. Some medications used to treat schizophrenia inhibit the replication of T. gondii in cell culture. Establishing the role of T. gondii in the etiopathogenesis of schizophrenia might lead to new medications for its prevention and treatment. [Abstract]

Brown AS, Schaefer CA, Quesenberry CP, Liu L, Babulas VP, Susser ES
Maternal exposure to toxoplasmosis and risk of schizophrenia in adult offspring.
Am J Psychiatry. 2005 Apr;162(4):767-73.
OBJECTIVE: The authors examined the relationship between maternal antibody to toxoplasmosis and the risk of schizophrenia and other schizophrenia spectrum disorders in offspring. Toxoplasmosis is known to adversely affect fetal brain development. METHOD: In a nested case-control design of a large birth cohort born between 1959 and 1967, the authors conducted serological assays for Toxoplasma antibody on maternal serum specimens from pregnancies giving rise to 63 cases of schizophrenia and other schizophrenia spectrum disorders and 123 matched comparison subjects. Toxoplasma immunoglobulin (Ig)G antibody was quantified by using the Sabin-Feldman dye test. The Ig titers were classified into three groups: negative (<1:16) (reference), moderate (1:16-1:64), and high (> or =1:128). RESULTS: The adjusted odds ratio of schizophrenia/schizophrenia spectrum disorders for subjects with high maternal Toxoplasma IgG antibody titers was 2.61 (95% confidence interval=1.00-6.82). There was no association between moderate Toxoplasma Ig antibody titers and the risk of schizophrenia/spectrum disorders. CONCLUSIONS: These findings suggest that maternal exposure to toxoplasmosis may be a risk factor for schizophrenia. The findings may be explained by reactivated infection or an effect of the antibody on the developing fetus. Given that toxoplasmosis is a preventable infection, the findings, if replicated, may have implications for reducing the incidence of schizophrenia. [Abstract]

Bachmann S, Schröder J, Bottmer C, Torrey EF, Yolken RH
Psychopathology in first-episode schizophrenia and antibodies to Toxoplasma gondii.
Psychopathology. 2005 Mar-Apr;38(2):87-90.
OBJECTIVE: Environmental factors such as infectious agents may contribute to the psychopathology and aetiology of schizophrenia. Toxoplasma gondii (TG) is a candidate infectious agent as it is known to replicate within the human central nervous system and to alter behaviour in experimental animals. METHOD: The relationship between antibodies to TG and psychopathological symptoms was examined in 34 first-episode patients with schizophrenia. RESULTS: Results of regression analyses revealed that symptoms on admission, predictors of outcome, age and family history of psychiatric disease influenced the levels of antibodies to TG. CONCLUSIONS: These results indicate that TG infections may play a role in the clinical manifestation of psychopathology in a subgroup of patients with schizophrenia. [Abstract]

Leweke FM, Gerth CW, Koethe D, Klosterkötter J, Ruslanova I, Krivogorsky B, Torrey EF, Yolken RH
Antibodies to infectious agents in individuals with recent onset schizophrenia.
Eur Arch Psychiatry Clin Neurosci. 2004 Feb;254(1):4-8.
We investigated the levels of antibodies to infectious agents in the serum and cerebral spinal fluids (CSFs) of individuals with recent onset schizophrenia and compared these levels to those of controls without psychiatric disease. We found that untreated individuals with recent onset schizophrenia had significantly increased levels of serum and CSF IgG antibody to cytomegalovirus and Toxoplasma gondii as compared to controls. The levels of serum IgM class antibodies to these agents were not increased. Untreated individuals with recent onset schizophrenia also had significantly lower levels of serum antibody to human herpesvirus type 6 and varicella zoster virus as compared to controls. Levels of antibodies to herpes simplex virus type 1, herpes simplex virus type 2, and Epstein Barr virus, and did not differ from cases and controls.We also found that treatment status had a major effect on the levels of antibodies in this population. Individuals who were receiving treatment had lower levels of antibodies to cytomegalovirus and Toxoplasma gondii, and higher levels of serum antibodies to human herpesvirus type 6 as compared to untreated individuals. The level of antibodies to Toxoplasma and human herpesvirus type 6 measured in treated individuals did not differ from the levels measured in controls. In the case of cytomegalovirus, the levels of CSF antibodies in treated individuals did not differ from those of controls, while the level of serum IgG antibodies to CMV remained slightly greater than controls in this population.Our studies indicate that untreated individuals with recent onset schizophrenia have altered levels of antibodies to cytomegalovirus, Toxoplasma gondii, and human herpesvirus type 6 while the levels of these antibodies in treated individuals with recent onset schizophrenia are similar to those of controls. These findings indicate that infectious agents may play a role in the etiopathogenesis of some cases of schizophrenia. [Abstract]

Yolken RH, Bachmann S, Ruslanova I, Lillehoj E, Ford G, Torrey EF, Schroeder J, Rouslanova I
Antibodies to Toxoplasma gondii in individuals with first-episode schizophrenia.
Clin Infect Dis. 2001 Mar 1;32(5):842-4.
We employed enzyme immunoassay (EIA) and Western blotting techniques to measure the level of antibodies to Toxoplasma gondii proteins in serum samples from 38 individuals undergoing their first episode of schizophrenia and from a group of matched control subjects. We found that the individuals with first-episode schizophrenia had significantly increased levels of IgG, IgM, and IgA class antibodies to Toxoplasma proteins, as compared with the control subjects. [Abstract]

Jones-Brando L, Torrey EF, Yolken R
Drugs used in the treatment of schizophrenia and bipolar disorder inhibit the replication of Toxoplasma gondii.
Schizophr Res. 2003 Aug 1;62(3):237-44.
The exact mechanisms of action of some antipsychotics and mood stabilizers have not been elucidated. Response to these medications can vary among individuals. Recent studies indicate that infection with the parasite Toxoplasma gondii may contribute to the symptoms of schizophrenia in some individuals. We investigated commonly used antipsychotic and mood stabilizing medications for their ability to inhibit the replication of this organism.We employed a system for testing compounds for in vitro activity against T. gondii. Human fibroblasts (HFF) were treated with test compounds and then exposed to Toxoplasma that has been genetically modified to express cytoplasmic beta-galactosidase. Inhibition by the drugs was determined by spectrophotometric analysis of colorimetric reactions.We tested 12 neuroleptic compounds and found that of these, the antipsychotic haloperidol and the mood stabilizer valproic acid most effectively inhibit Toxoplasma growth in vitro. Valproic acid inhibited the parasite at a concentration below that found in the cerebrospinal fluid and blood of individuals being treated with this medication and displayed synergistic activity with haloperidol and with trimethoprim, an antibiotic commonly used to treat Toxoplasma infections.Several medications used to treat schizophrenia and bipolar disorder have the ability to inhibit the in vitro replication of T. gondii. [Abstract]

Dickerson FB, Boronow JJ, Stallings CR, Origoni AE, Yolken RH
Reduction of symptoms by valacyclovir in cytomegalovirus-seropositive individuals with schizophrenia.
Am J Psychiatry. 2003 Dec;160(12):2234-6.
OBJECTIVE: The study was an investigation of the effect of the antiviral medication valacyclovir on the symptoms of outpatients with persistent schizophrenia. METHOD: Oral valacyclovir, 1 g twice daily, was administered to 65 outpatients over 16 weeks along with their usual psychiatric medications. Changes in psychiatric symptoms were measured with the Positive and Negative Syndrome Scale and were tested for correlations with antibodies to potentially neurotropic human herpesviruses, as measured by immunoassay before the start of the therapy. RESULTS: There was a significant improvement in the psychiatric symptoms of individuals who were seropositive for cytomegalovirus. Improvement was not associated with antibodies to other herpesviruses or to a range of demographic and clinical variables. CONCLUSIONS: The replication of cytomegalovirus may contribute to the symptoms of schizophrenia in some individuals. [Abstract]

Yolken R
Viruses and schizophrenia: a focus on herpes simplex virus.
Herpes. 2004 Jun;11 Suppl 283A-88A.
Various factors have been implicated in the pathogenesis of schizophrenia. Evidence for an infectious cause includes the 5-8% increased risk among those born in the winter-spring months, when infectious diseases are more prevalent and at times when other infections (measles, varicella, poliomyelitis) show increased activity. Herpes simplex virus (HSV) has been implicated in schizophrenia as it has a tropism for the nervous system and is capable of replication in the brain. Although post-mortem studies of brain tissue of schizophrenic patients have failed to detect the virus, these studies have been hampered by the unknown cellular localization of HSV genomes and by attempting to detect the virus years after the symptom onset. A more recent, nested, case-control study evaluated pregnant women between 1959 and 1966 and identified 27 surviving offspring who were later diagnosed with schizophrenia. Analysis of stored blood samples showed an association between high levels of maternal antibody to HSV-2 and subsequent development of adult psychosis. No association was found between HSV-1 infection and psychosis. There is also evidence that human endogenous retroviruses (HERVs) may play a role in schizophrenia, as antibodies to these agents have been found at a greater frequency in the sera of affected individuals compared with controls. This is supported by the presence of reverse transcriptase, a retroviral marker, at levels four times higher in the cerebrospinal fluid (CSF) of people with recent onset schizophrenia compared with controls, and by its elevated presence in long-term schizophrenic patients. Further research to investigate the relationship between virus infection and schizophrenia is warranted. [Abstract]

Fukuda R, Sasaki T, Kunugi H, Nanko S
No changes in paired viral antibody titers during the course of acute schizophrenia.
Neuropsychobiology. 1999;40(2):57-62.
Although there have been many studies surveying the prevalence of specific viral antibodies in a large cohort of patients with schizophrenia, changes in antibody levels during the course of acute illness have not been fully investigated. We conducted a preliminary study investigating levels of antibodies to 5 herpesviruses (herpes simplex virus type 1, cytomegalovirus, Epstein-Barr virus, varicella-zoster virus and human herpesvirus type 6) and 6 other viruses (measles, rubella, mumps, influenza A and B and Japanese encephalitis viruses) in paired sera of 8 patients with acute onset or exacerbation of schizophrenia. Assay for specific immunoglobulin M (IgM) antibody was also performed for herpesviruses and mumps. Neither any relevant change in antibody levels nor appearance of specific IgM antibody was observed for any of the viruses in any of the patients investigated. It is unlikely that the active infection or reactivation of these viruses has direct causal relationship to schizophrenia in these patients. [Abstract]

Fux M, Sarov I, Ginot Y, Sarov B
Herpes simplex virus and cytomegalovirus in the serum of schizophrenic patients versus other psychosis and normal controls.
Isr J Psychiatry Relat Sci. 1992;29(1):33-5.
One hundred and thirty eight subjects were examined for presence of antibodies by immunoperidose assay (IPA). The frequency of Cytomegalovirus (CMV) and Herpes Simplex Virus (HSV) antibody of 48 schizophrenic inpatients was compared to 48 inpatients with other psychosis and to 48 staff controls. No differences were found between schizophrenic and control groups. [Abstract]

Pelonero AL, Pandurangi AK, Calabrese VP
Serum IgG antibody to herpes viruses in schizophrenia.
Psychiatry Res. 1990 Jul;33(1):11-7.
Immunoglobulin measurements have provided indirect evidence to suggest that viruses may play an etiologic role in schizophrenia. The authors review the conflicting studies and report their own measurements of serum antibody absorbance to five viral antigens using an ELISA technique in 38 schizophrenic patients and 22 matched controls. For herpes simplex virus, 12 subjects (32%) had antibody levels more than 2 SD above the control mean. [Abstract]

Buka SL, Tsuang MT, Torrey EF, Klebanoff MA, Bernstein D, Yolken RH
Maternal infections and subsequent psychosis among offspring.
Arch Gen Psychiatry. 2001 Nov;58(11):1032-7.
BACKGROUND: We tested the hypothesis that maternal infections during pregnancy are associated with the subsequent development of schizophrenia and other psychoses in adulthood. METHODS: We conducted a nested case-control study of 27 adults with schizophrenia and other psychotic illnesses and 54 matched unaffected control subjects (matched for sex, ethnicity, and date of birth) from the Providence, RI, cohort of the Collaborative Perinatal Project. We retrieved stored blood samples that had been obtained from these mothers at the end of pregnancy. These samples were analyzed for total class-specific immunoglobulins and for specific antibodies directed at recognized perinatal pathogens capable of affecting brain development. RESULTS: Maternal levels of IgG and IgM class immunoglobulins before the mothers were delivered of their neonates were significantly elevated among the case series (t = 3.06, P =.003; t = 2.93, P =.004, respectively, for IgG and IgM immunoglobulin-albumin ratios). Secondary analyses indicated a significant association between maternal antibodies to herpes simplex virus type 2 glycoprotein gG2 and subsequent psychotic illness (matched t test = 2.43, P =.02). We did not find significant differences between case and control mothers in the serum levels of IgA class immunoglobulins, or in specific IgG antibodies to herpes simplex virus type 1, cytomegalovirus, Toxoplasma gondii, rubella virus, human parvovirus B19, Chlamydia trachomatis, or human papillomavirus type 16. CONCLUSIONS: The offspring of mothers with elevated levels of total IgG and IgM immunoglobulins and antibodies to herpes simplex virus type 2 are at increased risk for the development of schizophrenia and other psychotic illnesses in adulthood. [Abstract]

Dickerson FB, Boronow JJ, Stallings C, Origoni AE, Ruslanova I, Yolken RH
Association of serum antibodies to herpes simplex virus 1 with cognitive deficits in individuals with schizophrenia.
Arch Gen Psychiatry. 2003 May;60(5):466-72.
BACKGROUND: Cognitive deficits are a characteristic feature of schizophrenia and contribute to the profound disabilities associated with this illness. Some of the cognitive deficits that occur in individuals with schizophrenia are similar to those found in individuals who have recovered from central nervous system infections with human herpesviruses. METHODS: We measured cognitive functioning and serologic evidence of infection with human herpesviruses in 229 outpatients with schizophrenia. We evaluated cognitive functioning with the Repeatable Battery for the Assessment of Neuropsychological Status. For each patient, serum IgG class antibodies with specificities for the following potentially neurotropic human herpesviruses were measured by means of a solid-phase immunoassay: herpes simplex viruses 1 and 2, cytomegalovirus, Epstein-Barr virus, human herpesvirus 6, and varicella-zoster virus. We determined the association between serologic evidence of herpesviruses infection and cognitive functioning by univariate and multivariate analyses, including demographic and clinical factors associated with cognitive functioning. RESULTS: We found that serologic evidence of infection with herpes simplex virus 1 is an independent predictor of cognitive dysfunction in individuals with schizophrenia. Discriminant function analysis indicated that much of the difference in cognitive functioning could be attributed to immediate memory. We found no significant association between cognitive dysfunction and serologic evidence of infection with other human herpesviruses. CONCLUSION: Serologic evidence of herpes simplex virus 1 infection is associated with cognitive impairment in schizophrenia. [Abstract]

Karlsson H, Bachmann S, Schröder J, McArthur J, Torrey EF, Yolken RH
Retroviral RNA identified in the cerebrospinal fluids and brains of individuals with schizophrenia.
Proc Natl Acad Sci U S A. 2001 Apr 10;98(8):4634-9.
Schizophrenia is a serious brain disease of uncertain etiology. A role for retroviruses in the etiopathogenesis of some cases of schizophrenia has been postulated on the basis of clinical and epidemiological observations. We found sequences homologous to retroviral pol genes in the cell-free cerebrospinal fluids (CSFs) of 10 of 35 (29%) individuals with recent-onset schizophrenia or schizoaffective disorder. Retroviral sequences also were identified in the CSFs of 1 of 20 individuals with chronic schizophrenia. However, retroviral sequences were not identified in any of the CSFs obtained from 22 individuals with noninflammatory neurological diseases or from 30 individuals without evidence of neurological or psychiatric diseases (chi(2) = 19.25, P < 0.001). The nucleotide sequences identified in the CSFs of the individuals with schizophrenia or schizoaffective disorder were related to those of the human endogenous retroviral (HERV)-W family of endogenous retroviruses and to other retroviruses in the murine leukemia virus genus. Transcription of RNA homologous to members of the HERV-W family of retroviruses also was found to be up-regulated differentially in the frontal cortex regions of brains obtained postmortem from individuals with schizophrenia, as compared with corresponding tissue from individuals without psychiatric diseases. The transcriptional activation of certain retroviral elements within the central nervous system may be associated with the development of schizophrenia in at least some individuals. The further characterization of retroviral elements within the central nervous system of individuals with schizophrenia might lead to improved methods for the diagnosis and management of this disorder. [Abstract]

Karlsson H, Schröder J, Bachmann S, Bottmer C, Yolken RH
HERV-W-related RNA detected in plasma from individuals with recent-onset schizophrenia or schizoaffective disorder.
Mol Psychiatry. 2004 Jan;9(1):12-3. [Abstract]

Lillehoj EP, Ford GM, Bachmann S, Schröder J, Torrey EF, Yolken RH
Serum antibodies reactive with non-human primate retroviruses identified in acute onset schizophrenia.
J Neurovirol. 2000 Dec;6(6):492-7.
Schizophrenia is a pervasive neuropsychiatric disease of uncertain etiology. Previous studies have postulated that retroviruses may contribute to the etiology of some cases of schizophrenia. We examined the possible relationship between retroviral infection and schizophrenia by measuring antibodies to a number of different primate retroviruses in the sera of individuals undergoing their first hospitalization for this disease. Sera from patients with first onset schizophrenia and matched healthy controls were analyzed by immunoblot and enzyme linked immunosorbent assays using purified retrovirus antigens to identify and quantify antibodies reactive with retrovirus proteins. A significantly increased incidence of antibodies reactive to gag encoded proteins of Mason-Pfizer monkey virus (MPMV), baboon endogenous virus (BaEV) and simian retrovirus type 5 (SRV-5) was observed in the sera of schizophrenia patients compared to controls. The reactivity of the cases and controls displayed the greatest differences in terms of antibodies to the proteins of Mason-Pfizer monkey virus. Employing an algorithm of enzyme linked immunosorbent assay reactivity followed by immunoblot confirmation, we found that MPMV antibodies in 28.9% of the individuals with first episode schizophrenia patients as compared to 3.7% of the unaffected controls (P<0.009, Fisher's Exact Test). These studies are consistent with the occurrence of retrovirus replication in some individuals who are undergoing their first episode of schizophrenia. [Abstract]

Yolken RH, Karlsson H, Yee F, Johnston-Wilson NL, Torrey EF
Endogenous retroviruses and schizophrenia.
Brain Res Brain Res Rev. 2000 Mar;31(2-3):193-9.
Retroviruses are biologically complex infectious agents which are capable of cellular infection and subsequent integration into the host genome. Retroviruses can exist in an endogenous form in which viral sequences are integrated into the human germline and are vertically transmitted in a Mendelian fashion. The transcriptional activation of these viral sequences in cells within the central nervous system can affect the transcriptional regulation of adjacent genes and result in alterations of neural functioning. This report discusses evidence for a possible role of endogenous retroviruses in the etiopathogenesis of schizophrenia and other human brain diseases. Evidence of endogenous retrovirus activity is manifested by the identification of viral sequences in the brains and cerebrospinal fluids of affected individuals. In addition, affected individuals display evidence of increased activity of virally-encoded reverse transcriptase. The identification of a retroviral component of schizophrenia would be consistent with genetic, environmental, and neurodevelopmental aspects of the disease process. The delineation of a role for retroviruses in disease pathogenesis might lead to new methods for the diagnosis and treatment of schizophrenia. [Abstract]

Deb-Rinker P, Klempan TA, O'Reilly RL, Torrey EF, Singh SM
Molecular characterization of a MSRV-like sequence identified by RDA from monozygotic twin pairs discordant for schizophrenia.
Genomics. 1999 Oct 15;61(2):133-44.
Retroviral-related amplicons were used in modified RDA to identify four sequences from affected members of three pairs of monozygotic twins discordant for schizophrenia. One sequence (schizophrenia associated retrovirus, SZRV-1, GenBank Accession No. AF135487) is characterized here. It is similar to two known sequences of retroviral origin: multiple sclerosis-associated retrovirus, MSRV (GenBank Accession No. AF009668), and ERV-9 (GenBank Accession No. S77575). It is present in multiple copies in the human genome and has been localized to six different chromosomal sites. A zooblot shows that this multicopy sequence is predominant in the primate lineage and present in rhesus monkeys and humans. SZRV-1 is expressed as a 9-kb RNA band in the placenta. This could offer support to the hypothesis that retroviral sequences transposing during fetal growth may alter neurodevelopmental genes and cause diseases, although its direct involvement in the causation of schizophrenia remains to be established. [Abstract]

Deb P, Klempan TA, O'Reilly RL, Singh SM
Search for retroviral related DNA polymorphisms using RAPD PCR in schizophrenia.
Biochim Biophys Acta. 1999 Feb 24;1453(2):216-20.
Random amplification of polymorphic DNA (RAPD) is widely used to detect polymorphisms in many organisms. Individual (or strain) specific amplified bands are generated with single or pairs of primers in PCR reactions and can serve as genetic markers. We have used this method to generate a large number of reproducible bands with single primers, random and retroviral related, on 92 human DNA samples. Theoretically, RAPD PCR presents a logical approach for assessing variability among individuals. We used ten retroviral related primers (12, 20 and 22 bp) and eight random primers (10 bp) to assess individual differences in the context of testing the retroviral hypothesis for schizophrenia. Three pairs of discordant monozygotic twins, four pairs of discordant full sibs and 53 schizophrenic individuals with 25 of their unrelated matched controls were analyzed. Ten of these primers resulted in a total of approx. 850 amplified bands (65-110 bands per primer). Almost all of these bands were identical among each individual analyzed. However, the results are inconclusive with respect to the retroviral hypothesis for schizophrenia. The general lack of RAPD polymorphism in this study may argue for mechanisms other than rearrangements such as inversions, associated with the evolution of the human genome. [Abstract]

Suvisaari J, Haukka J, Tanskanen A, Hovi T, Lönnqvist J
Association between prenatal exposure to poliovirus infection and adult schizophrenia.
Am J Psychiatry. 1999 Jul;156(7):1100-2.
OBJECTIVE: The authors' goal was to determine whether there is an association between prenatal exposure to poliovirus infection and later development of schizophrenia. METHOD: All Finnish patients born between 1951 and 1969 with discharge diagnoses of schizophrenia (N = 13,559) were identified from the Finnish Hospital Discharge Register. Information on the monthly number of cases of paralytic poliomyelitis was obtained for each province in Finland. The authors analyzed the incidence of births of individuals who later developed schizophrenia by using a Poisson regression model with year and place of birth, age, sex, season of birth, and smoothed incidence of poliomyelitis in different gestational periods as explanatory variables. RESULTS: An association between the incidence of poliomyelitis and the incidence of births 5 months later of individuals who later developed schizophrenia was observed. Without controlling for seasonality, the effect was significant throughout the second trimester. CONCLUSIONS: Second-trimester exposure to poliovirus infection may increase the risk for the later development of schizophrenia. [Abstract]

Squires RF
How a poliovirus might cause schizophrenia: a commentary on Eagles' hypothesis.
Neurochem Res. 1997 May;22(5):647-56.
John M. Eagles suggested that polioviruses might cause schizophrenia because 1) several reports of a recent decline in the incidence of schizophrenia coinciding with the introduction of polio vaccination, 2) the observed winter excesses in schizophrenic births (in temperate climates) could be explained by fetal exposure to poliovirus during the second trimester of gestation which would occur during the summer when polio epidemics are most frequent, 3) there are increased rates of schizophrenia among immigrants to the UK from regions of the world with low frequencies if immunity to polioviruses, 4) there may be genetic variants in the poliovirus receptor gene that could increase susceptibility to poliovirus infection (1). The large discordance rates for schizophrenia in monozygotic twin pairs indicate the existence of both genetic and environmental factors. Numerous genetic studies indicate an interaction of several genes in the etiology of schizophrenia. These genes may encode a family of poliovirus receptor subunits, various active combinations of which are expressed on T-immunocytes, monocytes, endothelial cells, and limited populations of (glutamatergic?) neurons. The poliovirus receptor on the T-cell may require both a specific combination of V segments of the T-cell antigen receptor, as well as a specific major histocompatibility (MHC) antigen, acting in concert to infect monocytes, the primary transporter of poliovirus from blood into the brain. The very large discordance rates for schizophrenia that probably exist for dichorionic-monozygotic twins (about 90%), as well as the much smaller discordance rates for monochorionic-monozygotic twins (about 40%), may be due to several allelic exclusion events expressed both in T-cells and possibly in certain neurons. A child who has lost some glutamatergic neurons due to viral infection during the second trimester of gestation, may be able to compensate for this deficit to a large extent by the super-abundance of excitatory synapses that exists in the brain until sexual maturity, at which time a selective loss of excitatory (mainly glutamatergic) synapses occurs together with hormonally induced changes in behavior, leading to a much increased risk of a psychotic episode. [Abstract]

Eagles JM
Are polioviruses a cause of schizophrenia?
Br J Psychiatry. 1992 May;160598-600.
Pre-natal infection with polioviruses could contribute to the subsequent development of schizophrenia. The hypothesis draws support from the declining incidence of schizophrenia, the excess of schizophrenic winter births, and the increased rates of schizophrenia among West Indian immigrants. There are parallels with other late sequelae of poliovirus infections. These postulations generate a testable hypothesis of a genetic link between schizophrenia and susceptibility to poliomyelitis. [Abstract]

Torrey EF, Rawlings R, Waldman IN
Schizophrenic births and viral diseases in two states.
Schizophr Res. 1988 Jan-Feb;1(1):73-7.
In order to investigate a possible relationship between schizophrenic births and viral diseases, the birth month and year of all state hospital admissions for schizophrenia in Connecticut and Massachusetts from 1973-1974 were compared with the occurrence of reportable viral diseases for 1920-1955. Data was statistically examined by time series using spectral analysis. Statistically significant coherences were found between schizophrenic births and measles (both states), varicella-zoster (Connecticut) and polio (Connecticut). Influenza just missed statistical significance. No temporal relationship between schizophrenic births and rubella or mumps was found. The results are compared with similar studies in Minnesota and Finland. Definitive explanations for the observed relationships are precluded by the emerging complexity of virus-CNS interactions. A triggering of immune dysfunction by the infectious agents is proposed as the most reasonable explanation. [Abstract]

Brown AS, Cohen P, Harkavy-Friedman J, Babulas V, Malaspina D, Gorman JM, Susser ES
A.E. Bennett Research Award. Prenatal rubella, premorbid abnormalities, and adult schizophrenia.
Biol Psychiatry. 2001 Mar 15;49(6):473-86.
BACKGROUND: Premorbid neurocognitive, neuromotor, and behavioral function tends to be disturbed in schizophrenia. We previously demonstrated that a birth cohort clinically and serologically documented with prenatal rubella evidenced a marked increase in risk of nonaffective psychosis. In our study, we examined whether rubella-exposed subjects destined to develop schizophrenia and other schizophrenia spectrum disorders (SSD), compared with exposed control subjects, had greater impairment in several premorbid functions. METHODS: Subjects were interviewed using a direct, comprehensive research assessment and diagnosed by consensus. We compared the degree of IQ decline, as well as premorbid neuromotor and behavioral dysfunction, between rubella-exposed subjects who developed schizophrenia spectrum psychosis (SSP) and exposed control subjects from the cohort. We also compared the gestational timing of rubella infection between the cases and control subjects. RESULTS: This rubella-exposed birth cohort evidenced a markedly increased risk of SSD (20.4% or 11/53). Rubella-exposed SSP cases, compared with rubella-exposed control subjects, demonstrated a decline in IQ from childhood to adolescence, and increased premorbid neuromotor and behavioral abnormalities. Moreover, it appears that early gestational rubella exposure may represent a period of increased vulnerability for SSD. CONCLUSIONS: These findings link a known prenatal exposure, a deviant neurodevelopmental trajectory in childhood and adolescence, and SSP in adulthood within the same individuals. [Abstract]

Rantakallio P, Jones P, Moring J, Von Wendt L
Association between central nervous system infections during childhood and adult onset schizophrenia and other psychoses: a 28-year follow-up.
Int J Epidemiol. 1997 Aug;26(4):837-43.
BACKGROUND: Maternal exposure to influenza epidemics during pregnancy may increase the risk of schizophrenia in the offspring. We investigated the association between central nervous system (CNS) infections defined prospectively up to the age of 14, and later onset of schizophrenia and other psychoses in the 1966 birth cohort in Northern Finland, which covers 96% of all births in the area during that year. METHODS: Data regarding CNS infections were collected 1966-1980. Registered diagnoses of psychoses in 1982-1993 were validated on DSM-III-R criteria. RESULTS: Out of 11,017 subjects, 145 had suffered a CNS infection during childhood, 102 of them a viral infection, 76 had DSM-III-R schizophrenia and 53 some other psychosis. Four cases of schizophrenia had suffered viral CNS infection and two cases of other psychosis bacterial infection. When neurological abnormalities and father's social class were adjusted odds ratio (OR) of schizophrenia after viral CNS infection was 4.8 (95% confidence intervals [CI] : 1.6-14.0); the other significant risk factors being intelligence quotient (IQ) < 85, perinatal brain damage and male sex but not epilepsy. Similarly adjusted OR of other psychoses was 6.9 (95% CI: 1.4-32.8) after bacterial CNS infection; the other significant risk factors being IQ < 85 and severe hearing defect. Two of the live viral infections were caused by Coxsackie B5 during an epidemic in which 16 neonates were infected together. CONCLUSIONS: Central nervous system infections during childhood clearly carried an increased risk of adult onset schizophrenia or other psychoses, viral infections being important for schizophrenia, particularly Coxsackie B5 during the newborn period. [Abstract]

Stöber G, Franzek E, Beckmann H, Schmidtke A
Exposure to prenatal infections, genetics and the risk of systematic and periodic catatonia.
J Neural Transm. 2002 May;109(5-6):921-9.
The meaning of heterogeneity in schizophrenia and the impact of genetic and environmental factors on etiology are a matter of continuous debate in psychiatric research. Different clinical and birth history variables were investigated in a sample of 68 patients with chronic catatonic schizophrenia according to DSM III-R, classified into Leonhard's systematic schizophrenia (n = 32) and periodic catatonia (n = 36). Parental transmission of the disease was evident in 44% of the periodic catatonia cases compared to one case in systematic catatonia (3%; p = 0.0003). In systematic catatonia, 34% of the index cases were exposed to prenatal infections compared to 8% in periodic catatonia (p = 0.008). Using logistic regression analysis exposure to gestational maternal infections predicted diagnosis of systematic catatonia at p = 0.008, and parental psychosis predicted diagnosis of periodic catatonia in the index cases at p = 0.0001. The latter finding is substantiated by the recent mapping of a periodic catatonia-susceptibility locus on chromosome 15q15 with evidence for autosomal dominant transmission. These findings support the hypothesis that distinct schizophrenia phenotypes are based on different etiological mechanisms. [Abstract]

Koponen H, Rantakallio P, Veijola J, Jones P, Jokelainen J, Isohanni M
Childhood central nervous system infections and risk for schizophrenia.
Eur Arch Psychiatry Clin Neurosci. 2004 Feb;254(1):9-13.
Central nervous system (CNS) viral infections have been suggested to increase the risk of schizophrenia, although most of the evidence is indirect and comes from rather few studies on exposure to various infections in general. In the Northern Finland 1966 Birth Cohort the association between schizophrenia and other psychoses and childhood CNS infections has been analysed, and in this paper we present the follow-up results up to the end of 1994 and 1997.Data regarding the infections were collected prospectively between 1966-1980 and data on psychoses from 1982. The registered psychiatric diagnoses were validated using the DSM-III-R classification. Out of the 11017 subjects (96% of all births in that year) 145 had suffered a CNS infection during childhood, which in 102 cases was a viral infection. In the follow-up to the end of 1994, 76 had schizophrenia, and their number increased to 100 to the end of 1997. In addition, up to the end of 1994, 52 patients had a non-schizophrenic psychosis. Four cases in the schizophrenia patient group and none of the patients with other psychosis had suffered a viral CNS infection. None of the schizophrenia cases and two of the patients with other psychosis had had a bacterial infection. The adjusted odds ratio for schizophrenia after a viral CNS infection was 4.8 (95% confidence intervals [CI] 1.6-14.0) in the follow-up to the end of 1994 and 2.5 (0.9-7.0) in the follow-up to the end of 1997. The clinical course variables did not differ between the schizophrenia patients with or without CNS infection. Our results suggest that viral CNS infections during childhood may have a role as a risk factor for schizophrenia. Their role may be modest at the population level due to their relative rareness. [Abstract]

Suvisaari J, Mautemps N, Haukka J, Hovi T, Lönnqvist J
Childhood central nervous system viral infections and adult schizophrenia.
Am J Psychiatry. 2003 Jun;160(6):1183-5.
OBJECTIVE: An earlier Finnish cohort study suggested that childhood viral CNS infections are associated with a fivefold increased odds of developing schizophrenia in adulthood. The authors sought to replicate this finding. METHOD: From the archives of the Department of Virology of the National Public Health Institute in Finland, 320 individuals born between 1960 and 1976 who had suffered virologically confirmed CNS infections before their 15th birthdays were identified. Of the infections, 202 had been caused by enteroviruses. The sample was followed up in the 1969-2000 records of the National Hospital Discharge Register of Finland to identify all cases of schizophrenia that emerged. RESULTS: The cumulative incidence of schizophrenia was 0.94% in the whole sample and 0.99% among individuals who had suffered enteroviral infections. These rates are comparable to that found in the general population. CONCLUSIONS: Childhood viral CNS infections were not associated with increased risk of schizophrenia. [Abstract]

[Concentration and protein composition of circulating immune complexes in the blood of patients with schizophrenia and subjects with positive familial history of disease]
Zh Nevrol Psikhiatr Im S S Korsakova. 2005;105(4):55-60.
A comparative study of blood serum concentrations and pathogenic properties of circulating immune complexes (CIC), along with identification of their protein composition, was conducted in 45 patients with schizophrenia, 15 their healthy relatives and 39 normal controls. In patients and their relatives, mean concentration of small CIC was within the normal range, while concentrations of giant, large and middle CIC were higher than those of the controls (p<0.001). Over 80% of schizophrenic patients and their relatives had pathogenic immune complexes in the circulation. Clinical and immunologic analysis of patients with schizophrenia revealed a correlation between the illness duration and CIC concentration for all sizes. Smokers had significantly lower levels of small CIC comparing to non-smokers. Determination of CIC composition in patients and relatives revealed a presence of specific proteins in the immune complexes with molecular weights of 36 and 25 kDa. The results suggest genetic determination of autoimmune processes in schizophrenia. [Abstract]

Henneberg AE, Horter S, Ruffert S
Increased prevalence of antibrain antibodies in the sera from schizophrenic patients.
Schizophr Res. 1994 Dec;14(1):15-22.
The pathogenesis of schizophrenia is still unknown. In a previous study we found antibrain antibodies in the sera of schizophrenic patients, but not in normal controls. Therefore we have further examined the sera of schizophrenic patients versus normal controls, increasing the number of brain areas, to explore whether certain areas were involved more often than others in the antibody binding process. The sera of 50 patients suffering from an acute episode of schizophrenia (classified by DSM III-criteria) were tested. 70% of the patients showed antibody binding, while only 12% of the age- and sex-matched controls were positive. The binding was mediated by IgG- as well as IgM-antibodies. Amygdala, frontal cortex, cingulate gyrus, and septal area were the prominent targets, while hippocampus, parahippocampal gyrus, entorhinal cortex, putamen, mamillary bodies and head of the caudate nucleus were involved to a lesser degree. Binding was not present to nucleus olivaris, to the thyroid gland or to HEp-2 cells, which we included to test for unspecific antinuclear factors. Longterm studies of schizophrenic patients and biochemical analyses of the antigen(s) involved are in progress. [Abstract]

Henneberg AE, Ruffert S, Henneberg HJ, Kornhuber HH
Antibodies to brain tissue in sera of schizophrenic patients--preliminary findings.
Eur Arch Psychiatry Clin Neurosci. 1993;242(5):314-7.
The sera of 30 patients suffering from schizophrenia (DSM III) and 30 neurological controls were tested for antibrain antibodies in a blind indirect immunofluorescence assay. We found IgG- and IgM-binding in the sera of 22 patients, but only 4 out of the 30 age- and sex-matched controls. The binding was mainly directed to neurons from the frontal cortex and septal areas, areas, which are regarded as important in the development of schizophrenic illness. These preliminary data are presented, to encourage other immunological studies in schizophrenia research. [Abstract]

Knight JG, Knight A, Menkes DB, Mullen PE
Autoantibodies against brain septal region antigens specific to unmedicated schizophrenia?
Biol Psychiatry. 1990 Sep 15;28(6):467-74.
Heath et al. (1989) reported that serum from 96% of unmedicated schizophrenic patients contained IgG autoantibodies specific for the septal region of rhesus monkey brain, compared with 0% of nonschizophrenic control subjects and 6% of schizophrenic patients who were on neuroleptic medication. Using the same technique of crossed immunoelectrophoresis, we have tried to replicate this finding. In contrast to the original report, we observed "positive" precipitin arcs with IgG concentrates from all 14 serum samples tested. The failure of immunoelectrophoretic methods to provide convincing evidence of pathogenic autoantibodies in schizophrenia in no way detracts from the hypothesis that autoimmune processes are involved in some forms of schizophrenia. Such methods have not proved useful in established autoimmune diseases such as Graves' disease and myasthenia gravis in which the pathogenic autoantibodies against cell-surface receptors can only be detected by assays which measure functional interactions with such receptors. [Abstract]

Heath RG, McCarron KL, O'Neil CE
Antiseptal brain antibody in IgG of schizophrenic patients.
Biol Psychiatry. 1989 Mar 15;25(6):725-33.
On the hypothesis that schizophrenia is an immunological disorder in which antibody is produced against a unique antigen sequestered principally or exclusively in the septal region of the brain, we used crossed-immunoelectrophoresis (CIE) to evaluate reactivity of a gamma G immunoglobulin (IgG) fraction from serum of schizophrenic patients and nonschizophrenic control subjects with homogenates of tissues of septal region, hippocampus, vermal cerebellum, frontal cortex, and liver of rhesus monkeys. When IgG fractions of unmedicated schizophrenic patients and schizophrenic patients who had received neuroleptic medication for less than 24 hr were tested against septal region homogenate, a precipitin arc was identified, indicating a positive result, with more than 95% of the fractions. In contrast, IgG fractions of schizophrenic patients who had received neuroleptic medication for more than 24 hr were rarely positive. When schizophrenic fractions that tested positive against septal region homogenate were tested against homogenates of the other tissues, they were negative. Fractions of all nonschizophrenic control subjects were negative against all homogenates. [Abstract]

Mazeh D, Sirota P, Patya M, Novogrodsky A
Antibodies to neuroblastoma cell line proteins in patients with schizophrenia.
J Neuroimmunol. 1998 Apr 15;84(2):218-22.
The presence of antibodies against neural antigens was investigated in the serum of patients with schizophrenia, major depression and normal controls. Different immunological abnormalities, humoral and cellular, were reported in schizophrenia and major depression. The pathogenesis of schizophrenia is multifactorial. An autoimmune mechanism was suggested as a possible factor. We tested the serum of 26 patients with schizophrenia, eight patients with major depression and 22 normal controls. The serum samples were tested for antibody binding to protein extracts of IMR-32 neuroblastma cell line using Western blot analysis. Immunoglobulins of eight patients with schizophrenia (30.71%) reacted with a protein of 80-85 kDa. Serum samples from subjects of other groups did not react with this protein. Sera of all patients with major depression but one, and all normal controls reacted with HSP 60 kDa to different extent. This is an apparent discrepancy with the findings of Kilidireas et al. [Kilidireas, K., Latov, N., Strauss, D.H., Gorig, A.D., Hashim, G.A., Gorman, J.M., Sadig, S.A., 1992. Antibodies to the human 60 kDa heat shock protein in patients with schizophrenia. Lancet 340, 569-572.] who demonstrated the presence of antibodies against HSP 60 kDa in 44% of patients with schizophrenia tested and 8% of normal subjects. HSP 60 kDa is an antigen of many pathogens and antibodies against it might be a result of an infection and cannot be a good indicator for an autoimmune process. The presence of antibodies against a protein of 80-85 kDa should be investigated as a possible specific indicator. [Abstract]

Kilidireas K, Latov N, Strauss DH, Gorig AD, Hashim GA, Gorman JM, Sadiq SA
Antibodies to the human 60 kDa heat-shock protein in patients with schizophrenia.
Lancet. 1992 Sep 5;340(8819):569-72.
Immune mechanisms are thought to be important in a subpopulation of patients with schizophrenia. We examined the specificity of neural antibodies in patients with schizophrenia to identify a possible antigen. Serum antibodies from patients with schizophrenia and control subjects were tested for binding to protein extracts of human neuroblastoma cells by western blot. Protein antigens were characterised by aminoterminal and internal aminoacid sequence analysis. 14 of 32 (44%) otherwise healthy patients with schizophrenia had antibodies to a neuroblastoma protein of molecular weight 60 kDa. By partial sequence analysis, this protein was identified as the 60 kDa human heat-shock protein (hsp) that is the P1 mitochondrial protein, and which is 50% homologous to the mycobacterial 65 kDa hsp. Antigens that crossreact with hsp65 have been implicated in the pathogenesis of adjuvant-induced arthritis in rats and autoimmune diabetes in mice. Of 100 normal subjects or disease controls, antibodies to hsp60 were found in only 8 patients, all of whom had active infectious or inflammatory disease. Our results support the presence of abnormal immune reactivity involving hsp60 in a subset of patients with schizophrenia. The immune response may be related to the pathogenesis of the disease. [Abstract]

Yovel G, Sirota P, Mazeh D, Shakhar G, Rosenne E, Ben-Eliyahu S
Higher natural killer cell activity in schizophrenic patients: the impact of serum factors, medication, and smoking.
Brain Behav Immun. 2000 Sep;14(3):153-69.
Schizophrenia has been associated with altered immunity and reduced occurrence of autoimmune diseases and malignancies. A few studies in schizophrenic patients have assessed natural killer cell activity (NKA), but no consistent findings have emerged. However, NKA was assessed using standard procedures and in the absence of autologous serum and the various cytokines that modulate NKA and appear to be abnormal in schizophrenic patients. In the current study, therefore, the number of NK cells and the activity of the individual NK cell were assessed in whole blood shortly after blood withdrawal, in both the presence and the absence of autologous serum. Twenty-nine schizophrenic patients (11 nonmedicated), 8 nonschizophrenic control patients (bipolar and personality disorders), and 31 age-matched healthy controls were studied. Schizophrenic patients showed higher NKA per NK cell than controls and nonschizophrenic patients. This difference remained significant even when the nonmedicated schizophrenics, who showed the highest levels of NKA, were excluded. However, the increase in NKA was more pronounced in the presence of serum and was reduced to an insignificant level when serum was removed from the same samples. In both schizophrenic patients and controls, smokers and women showed lower NKA. Numbers of NK cells did not differ among groups, although medication affected blood concentration of other leukocytes. These findings indicate that the effects of serum factors, psychiatric medication, gender, and smoking should be considered when assessing NKA in schizophrenic patients. The observed higher NKA may help explain the surprising reports of low incidence of lung cancer and other malignancies in schizophrenic patients, despite their higher rate of smoking. [Abstract]

Zorrilla EP, Cannon TD, Gur RE, Kessler J
Leukocytes and organ-nonspecific autoantibodies in schizophrenics and their siblings: markers of vulnerability or disease?
Biol Psychiatry. 1996 Nov 1;40(9):825-33.
To determine whether leukocyte counts and organ-nonspecific autoantibodies mark familial vulnerability for schizophrenia and/or the disease itself, we examined 92 patients with schizophrenia and 94 unrelated, demographically balanced, healthy individuals. In addition, for 19 of the probands, one of their nonschizophrenia, full siblings also was recruited. At the time of the blood draw, most probands (87%) had been free of medications for a minimum of 2 weeks and about half were neuroleptic-naive, first-episode patients. Results indicate that a relative lymphopenia in the context of a relative granulocytosis appears to mark familial vulnerability for schizophrenia, whereas an absolute monocytosis appears to mark spectrum manifestations of the clinical phenotype. The former observation is consistent with the hypothesis that the etiology of schizophrenia is immunologically mediated, whereas the latter is consistent with emerging evidence that an inflammatory process is associated with the expression of the disorder. Neither antinuclear antibody nor rheumatoid factor emerged as liability or disease markers. [Abstract]

Borda T, Gomez R, Berría MI, Sterin-Borda L
Antibodies against astrocyte M1 and M2 muscarinic cholinoceptor from schizophrenic patients' sera.
Glia. 2004 Jan 15;45(2):144-54.
We demonstrated the presence of circulating antibodies from schizophrenic patients able to interact with cultured astrocytes activating muscarinic acetylcholine receptors (mAChRs). Sera and purified IgG from 15 paranoid schizophrenic and 15 age-matched normal subjects were studied by indirect immunofluorescence (IFI), flow cytometry, dot blot, enzyme immunoassay (ELISA), and radioligand competition assays. Astrocyte membranes and/or a synthetic peptide, with identical amino acid sequence of human M(1) and M(2) mAChR, were used as antigens. By IFI and flow cytometry procedures, we proved that serum purified IgG fraction from schizophrenic patients, reacted to astrocyte cell surface. The same antibodies were able to inhibit the binding of the specific mAChR radioligand (3)H-QNB. Using synthetic peptide for dot blot and ELISA, we demonstrated that these antibodies reacted against the second extracellular loop of human cerebral M(1) and M(2) mAChR. Also, the corresponding affinity-purified antipeptide antibody displayed an agonistic-like activity associated to specific M(1) and M(2) mAChR activation, increasing inositol phosphates accumulation and decreasing cyclic AMP production, respectively. This article gives support to the participation of an autoimmune process in schizophrenia disease. [Abstract]

Mukherjee S, Mahadik SP, Korenovsky A, Laev H, Schnur DB, Reddy R
Serum antibodies to nicotinic acetylcholine receptors in schizophrenic patients.
Schizophr Res. 1994 May;12(2):131-6.
Although elevated serum levels of antibodies to the nicotinic acetylcholine receptor (nAChR) have been reported in neuroleptic treated patients with tardive dyskinesia, such antibodies have not been determined in comparable nondyskinetic patients. Using a toxin-binding inhibition assay, we examined serum anti-nAChR antibody levels in 17 DSM-III-R chronic schizophrenic patients, seven of whom had persistent tardive dyskinesia, and 10 normal controls. On the average, anti-nAChR antibody levels were significantly higher in schizophrenic patients than in normal controls, but but not differ between patients with and without tardive dyskinesia and was not related to age, sex, or duration of illness in patients. [Abstract]

Yamaguchi K, Sawada T, Naraki T, Igata-Yi R, Shiraki H, Horii Y, Ishii T, Ikeda K, Asou N, Okabe H, Mochizuki M, Takahashi K, Yamada S, Kubo K, Yashiki S, Waltrip RW, Carbone KM
Detection of borna disease virus-reactive antibodies from patients with psychiatric disorders and from horses by electrochemiluminescence immunoassay.
Clin Diagn Lab Immunol. 1999 Sep;6(5):696-700.
The prevalence of Borna disease virus (BDV)-specific antibodies among patients with psychiatric disorders and healthy individuals has varied in several reports using several different serological assay methods. A reliable and specific method for anti-BDV antibodies needs to be developed to clarify the pathological significance of BDV infections in humans. We developed a new electrochemiluminescence immunoassay (ECLIA) for the antibody to BDV that uses two recombinant proteins of BDV, p40 and p24 (full length). Using this ECLIA, we examined 3,476 serum samples from humans with various diseases and 917 sera from blood donors in Japan for the presence of anti-BDV antibodies. By ECLIA, 26 (3.08%) of 845 schizophrenia patients and 9 (3.59%) of 251 patients with mood disorders were seropositive for BDV. Among 323 patients with other psychiatric diseases, 114 with neurological diseases, 75 with chronic fatigue syndrome, 85 human immunodeficiency virus-infected patients, 50 with autoimmune diseases including rheumatoid arthritis and systemic lupus erythematosis and 17 with leprosy, there was no positive case except one case each with alcohol addiction, AIDS, and dementia. Although 19 (1.36%) of 1,393 patients with various ocular diseases, 10 (1.09%) of 917 blood donors, and 3 (4.55%) of 66 multitransfused patients were seropositive for BDV-specific antigen, high levels of seroprevalence in schizophrenia patients and young patients (16 to 59 years old) with mood disorders were statistically significant. The immunoreactivity of seropositive sera could be verified for specificity by blocking with soluble p40 and/or p24 recombinant protein. Anti-p24 antibody was more frequent than p40 antibody in most cases, and in some psychotic patients antibody profiles showed only p40 antibody. Although serum positive for both p40 and p24 antibodies was not found in this study, the p40 ECLIA count in schizophrenia patients was higher than that of blood donors. Furthermore, we examined 90 sera from Japanese feral horses. Antibody profiles of control human samples are similar to that of naturally BDV-infected feral horses. We concluded that BDV infection was associated in some way with psychiatric disorders. [Abstract]

Chen CH, Chiu YL, Shaw CK, Tsai MT, Hwang AL, Hsiao KJ
Detection of Borna disease virus RNA from peripheral blood cells in schizophrenic patients and mental health workers.
Mol Psychiatry. 1999 Nov;4(6):566-71.
Accumulating evidence suggests that Borna disease virus (BDV), a neurotropic, negative-stranded RNA virus, might be associated with certain human mental disorders. Several research groups reported that psychiatric patients had a significantly higher prevalence of BDV serum antibodies than normal controls. In addition, a significantly higher presence of BDV RNA from peripheral blood cells was identified in mental patients than in controls. In our previous study, we first identified the presence of BDV serum antibodies in a cohort of Chinese schizophrenic patients from Taiwan, and we also demonstrated a significantly higher seroprevalence of BDV antibodies among schizophrenic patients than in non-psychiatric controls. Prompted by the positive seroepidemiological result, we set out to investigate the detection of BDV RNA from the peripheral blood cells of our schizophrenic patients. By using the reverse transcription-polymerase chain reaction (RT-PCR) method, 10 out of 74 Chinese schizophrenic patients from Taiwan were found to have BDV RNA in their blood cells, whereas only one out of 69 controls was positive. The BDV RNA detection rate among schizophrenic patients was significantly higher than that in controls (14% vs 1.4%, P < 0.01). Furthermore, we studied the BDV RNA detection rate among mental health workers, and seven out of 45 mental health workers were found to have positive results. The prevalence rate was significantly higher than that in normal controls (15% vs 1.4%, P < 0.001), which lends further support to our previous finding that mental health workers have a significantly higher presence of BDV serum antibodies. In summary, our data support the finding that BDV infection might be a contributory factor to the pathogenesis of schizophrenia in the Chinese population. [Abstract]

Chen CH, Chiu YL, Wei FC, Koong FJ, Liu HC, Shaw CK, Hwu HG, Hsiao KJ
High seroprevalence of Borna virus infection in schizophrenic patients, family members and mental health workers in Taiwan.
Mol Psychiatry. 1999 Jan;4(1):33-8.
Borna disease virus (BDV), a negative-strand RNA virus, has been reported to be associated with severe psychiatric disorders. The association is mainly based on the findings that patients with schizophrenia and depression have a higher seroprevalence rate of BDV-specific antibodies than controls. In addition, psychiatric patients were also found to have a higher detection rate of BDV transcripts in their blood than controls. By using an improved Western blot analysis, we first demonstrated that Chinese schizophrenic patients from Taiwan also have a higher seroprevalence of BDV-specific antibodies than controls (12.1% vs 2.9%, P< 0.001), providing support to the positive association between BDV and psychiatric disorders in our population. Because of the contagious nature of viral infection, we further examined patients' family members and mental health workers, who have close contact with patients. We found that both groups also have a higher seroprevalence of BDV-specific antibodies, 12.1% and 9.8%, respectively, than controls. This finding provides some evidence for a possible human-to-human transmission of Borna disease virus. Our finding needs further independent verification from other research groups and the clinical relevance of this preliminary observation deserves further study. [Abstract]

Yang AY, Zhang FM, Li JH, Li GM, Ma PL, Gu HX, Ikuta K
[Detection of Borna disease virus-p24 specific antibody in the sera of schizophrenic patients of China by means of Western-blot]
Zhonghua Shi Yan He Lin Chuang Bing Du Xue Za Zhi. 2003 Mar;17(1):85-7.
BACKGROUND: To investigate whether Borna disease virus (BDV) infection is related to the schizophrenic patients from China. METHODS: A reliable Western-blot method for detection of BDV-p24 antibody was established by adjusting the reaction conditions of BDV-p24 recombinant protein and specific antibodies. The sera of schizophrenic patients and normal controls from Heilongjiang Province were screened for specific BDV-p24 antibody by this method, and the BDV-p24 antibody positive sera were confirmed by the Western-blot method with sera-GST protein absorption. RESULTS: Ten of 116 (8.6%) schizophrenic patients were found to be positive for BDV-p24 specific antibody, while no BDV-p24 specific antibody was found in sera of normal controls. CONCLUSIONS: The results demonstrate that the Borna disease virus infection also exists in China, and the infection is possibly associated with schizophrenia in some way. [Abstract]

Waltrip RW, Buchanan RW, Summerfelt A, Breier A, Carpenter WT, Bryant NL, Rubin SA, Carbone KM
Borna disease virus and schizophrenia.
Psychiatry Res. 1995 Jan 31;56(1):33-44.
The development of a new serological assay method to detect antibodies in human sera recognizing Borna disease virus (BDV) proteins and a clinical pilot study are presented. Psychiatric patients from a schizophrenia research clinic in Baltimore, Maryland, were examined for antibodies to BDV antigen with traditional indirect immunofluorescence assays (IFA) that used both single and double labeling techniques and also with a Western blot assay capable of detecting antibodies to the three BDV proteins from a human neuroblastoma cell line. Thirteen of 90 (14.4%) patients and 0/20 control subjects had antibodies that recognized more than one BDV protein on the Western blot. Three patients had antibodies that recognized all three BDV proteins. Magnetic resonance imaging assessments of the volume of the putamen (with controls for total cranial volume) differentiated BDV+ from BDV- patients, and there were trend differences for bilateral amygdalae and the left amygdala-hippocampal process. We conclude that: (1) the Western blot assay is superior to IFA assays in BDV serology studies, (2) detection of antibodies to more than one BDV protein is a useful working criterion for seropositivity, (3) the 14.5 kDa BDV protein is 10 times more predictive of seropositivity than either the 38/40 kDa or the 24 kDa protein, (4) there is tentative evidence for a schizophrenia-control difference in the prevalence of anti-BDV antibodies, and (5) it is likely that there are neuroanatomical/behavioral features that differentiate seropositive from seronegative schizophrenic patients. [Abstract]

Terayama H, Nishino Y, Kishi M, Ikuta K, Itoh M, Iwahashi K
Detection of anti-Borna Disease Virus (BDV) antibodies from patients with schizophrenia and mood disorders in Japan.
Psychiatry Res. 2003 Sep 30;120(2):201-6.
The relationship between infection with the Borna Disease Virus (BDV) and the clinical symptoms of schizophrenia and mood disorders (DMS-IV) was investigated. Western blotting techniques were used to examine anti-p10-BDV antibodies in serum from 32 patients with schizophrenia and 33 patients with mood disorders in Japan. The results showed that 1 out of 25 controls (4.0%), 7 out of 32 patients with schizophrenia (21.9%) and 9 out of 33 patients with mood disorders (27.3%) were positive for anti-BDV-p10 antibodies. Compared with levels of anti-BDV-p10 antibodies in controls, the production of anti-BDV-p10 antibodies failed to show a statistically significant relationship with schizophrenia but did show a significant relationship with mood disorder. The subgroup of schizophrenia patients with positive syndromes had a non-significantly higher frequency of anti-BDV-p10 antibodies than the subgroup of patients with negative syndromes. Similarly, the production of anti-BDV-p10 antibodies was non-significantly higher among patients with the unipolar subtype of mood disorder than in those with the bipolar subtype. [Abstract]

Selten JP, van Vliet K, Pleyte W, Herzog S, Hoek HW, van Loon AM
Borna disease virus and schizophrenia in Surinamese immigrants to the Netherlands.
Med Microbiol Immunol (Berl). 2000 Nov;189(2):55-7.
Borna disease virus (BDV) has been suggested to play a role in the etiology of schizophrenia. We tested the hypothesis that markers of BDV infection are more frequent in Surinamese immigrants to the Netherlands, diagnosed with schizophrenia, than in Dutch-born healthy subjects. For reasons that are poorly understood there is an increased incidence of schizophrenia in this immigrant group. Blood was obtained from 29 male schizophrenic patients (DSM-IV criteria) and from 26 healthy males. For detection of anti-BDV antibodies an indirect immunofluorescence assay (IFA) was performed. A nested, reverse-transcriptase-PCR, using primers specific for the p24 and p40 BDV genes, was used to determine BDV-RNA in peripheral blood mononuclear cells. Contrary to our expectations, the frequencies of BDV markers in the group of healthy subjects, as determined by IFA and both PCRs, exceeded that in the group of patients. The results do not support an association between markers of BDV infection in blood and schizophrenia. It is unlikely that the high incidence of schizophrenia in Surinamese immigrants is caused by BDV, but the small number of subjects examined do not warrant definitive conclusions. [Abstract]

Rybakowski F
[Transmission of Borna disease virus as etiopathogenetic factor in schizophrenia and affective disorders]
Psychiatr Pol. 1999 Nov-Dec;33(6):947-58.
Borna Disease Virus (BDV) is a negative single-stranded ribonucleic acid (RNA) virus, showing strong neurotropism. BDV may infect many different warm-blooded animal species, causing neurological and behavioral disorders. Seroepidemiological studies suggest the existence of human infections with BDV and their higher prevalence in psychiatric patients. Using different serological assays, anti-BDV antibodies were found in about 10%-20% of patients with schizophrenia, and in 1%-2% of the control group of healthy subjects. There are also reports on BDV antigens and BDV RNA in peripheral blood mononuclear cells of human subjects, and in the brain tissue examined during the autopsy in patients with psychiatric disorders. Higher prevalence of BDV infection markers was also found in the group of patients with affective illness. A hypothesis was put forward on the activation of BDV-infection in patients with affective illness during acute episode. There are also reports on higher BDV-seropositivity in various psychiatric disorders compared with healthy control subjects. It also would be purposeful to study a possibility of BDV infections in patients with psychiatric disturbances, having their onset in childhood or adolescence. [Abstract]

Iwata Y, Takahashi K, Peng X, Fukuda K, Ohno K, Ogawa T, Gonda K, Mori N, Niwa S, Shigeta S
Detection and sequence analysis of borna disease virus p24 RNA from peripheral blood mononuclear cells of patients with mood disorders or schizophrenia and of blood donors.
J Virol. 1998 Dec;72(12):10044-9.
Borna disease virus (BDV) p24 RNA was detected in the peripheral blood mononuclear cells (PBMCs) of psychiatric patients and blood donors by nested reverse transcriptase PCR (RT-PCR). The prevalences of BDV p24 RNA in patients with mood disorders (4%) and schizophrenia (4%) were not significantly different from that in blood donors (2%). This finding was inconsistent with previous reports that showed either a high prevalence or absence of BDV p24 RNA in patients with psychiatric disorders. The differences in BDV p24 RNA prevalence in these studies may be due to differences in the criteria for positivity, the number of PBMCs used for RNA extraction, or the amount of RNA tested for nested RT-PCR or to laboratory contamination. Sequence analysis of BDV p24 RNA from the PBMCs of patients and blood donors showed a high nucleotide sequence conservation but definite nucleotide mutations compared with horse BDV p24 RNA sequences. In comparison with human BDV p24 RNA sequences previously reported from Japan and Germany, there were several positions with silent nucleotide mutations among these clones. [Abstract]

Kim YK, Kim SH, Choi SH, Ko YH, Kim L, Lee MS, Suh KY, Kwak DI, Song KJ, Lee YJ, Yanagihara R, Song JW
Failure to demonstrate Borna disease virus genome in peripheral blood mononuclear cells from psychiatric patients in Korea.
J Neurovirol. 1999 Apr;5(2):196-9.
RNA, extracted from peripheral blood mononuclear cells (PBMC) obtained from 81 Korean psychiatric patients (39 with schizophrenia, 33 with bipolar affective disorders and nine with major depression), was analyzed for a 391-nucleotide, highly conserved region of the p24 protein-encoding ORF II of Borna disease virus (BDV), using nested reverse transcription-polymerase chain reaction (RT-PCR). BDV genomic RNA was not detected in PBMC from any of the 81 Korean psychiatric patients. These data do not support an etiologic association between BDV infection and neuropsychiatric disorders in humans. [Abstract]

Nakamura Y
[Isolation of Borna disease virus from the autopsy brain of a schizophrenia patient]
Hokkaido Igaku Zasshi. 1998 May;73(3):287-97.
Borna disease virus (BDV) causes a central nervous system disease in several vertebrate species which is characterized by behavioral disturbances. Seroepidemiological data suggested an association of BDV infection with certain human mental disorders, especially schizophrenia and depression. Here, BDV infection was examined in autopsy brain samples from 4 schizophrenia patients. Nested reverse transcriptase-polymerase chain reaction (RT-PCR) and in situ hybridization revealed BDV-RNA only in restricted regions (hippocampus, cerebellum, pons) of the autopsy brain samples from one but not other three patients. Histopathologically mild perivascular cuffing was observed in hippocampus, in which BDV-RNA was detected. Next, BDV isolation from the BDV-positive patient's brain region was carried out by intracranial inoculation of BDV-sensitive Mongolian gerbils with the patient's cerebellum and hippocampus homogenate. BDV-RNA signals were detected in the brain from inoculated gerbils at 20 days post-inoculation by nested RT-PCR. Further, the BDV-RNA positive brain from an inoculated gerbil was used for BDV isolation in cell culture. Serial passages with human oligodendroglioma (OL) cells allowed to establish persistent infection of BDV in the cells. [Abstract]

Waltrip RW, Buchanan RW, Carpenter WT, Kirkpatrick B, Summerfelt A, Breier A, Rubin SA, Carbone KM
Borna disease virus antibodies and the deficit syndrome of schizophrenia.
Schizophr Res. 1997 Feb 28;23(3):253-7.
We detected anti-Borna disease virus (BDV) antibodies at a 14.4% rate in patients with schizophrenia. The hypothesis of a higher rate of BDV seropositivity in deficit syndrome was borne out in a subset of 64 patients categorized according to the Schedule for the Deficit Syndrome with 5/15 seropositive deficit and 4/49 seropositive nondeficit (p < 0.05). This suggests that the antibodies and possibly a BDV-like virus are pathogenetically linked to this form of schizophrenia. [Abstract]

Iwahashi K, Watanabe M, Nakamura K, Suwaki H, Nakaya T, Nakamura Y, Takahashi H, Ikuta K
Positive and negative syndromes, and Borna disease virus infection in schizophrenia.
Neuropsychobiology. 1998;37(2):59-64.
The relationship between Borna disease virus (BDV) infection and positive and negative syndromes in schizophrenia was investigated. By nested RT-PCR and Western blotting, BDV-specific RNA and anti-BDV antibodies were examined in blood from 67 schizophrenic patients (DSM-III-R) in Japan, and the psychometric properties of the Positive and Negative Syndrome Scale (PANSS) were analyzed. There were significant (p < 0.05) differences in the composite index denoting the positive minus negative difference indicating a dominant contribution by negative items, and the proportion of negative type (positive minus negative value below zero) patients, between patients positive and negative for anti-BDV p24 antibodies. It is possible that BDV infection with induction of BDV p24 antibodies may be associated with negative syndromes in schizophrenic patients. [Abstract]

Iwahashi K, Watanabe M, Nakamura K, Suwaki H, Nakaya T, Nakamura Y, Takahashi H, Ikuta K
Clinical investigation of the relationship between Borna disease virus (BDV) infection and schizophrenia in 67 patients in Japan.
Acta Psychiatr Scand. 1997 Dec;96(6):412-5.
The relationship between Borna disease virus (BDV) infection and schizophrenia in the clinical time course was investigated. By nested reverse-transcribed polymerase chain reaction (RT-PCR) and Western blotting, BDV-specific RNA and anti-BDV antibodies were examined in the EDTA-treated blood from 67 schizophrenic patients (according to DSM-III-R) in Japan. A significantly higher proportion (45%) of anti-BDV antibody and/or BDV RNA carriers were found among these 67 schizophrenic patients than in 26 controls (0%). There were no apparent associations of BDV infection with age, age at onset, period of hospitalization, accompanying somatic diseases, a past history of tuberculosis, a history of transfusion, a family history, or doses of psychotropic drugs. It is possible that, at least, BDV infection in schizophrenic patients may not be a nosocomial (hospital-acquired) infection, although the route of BDV infection in humans remains unidentified. More studies on the relationship between BDV infection and clinical psychosomatic features should be performed in order to elucidate the pathogenesis of schizophrenia. [Abstract]

Horimoto T, Takahashi H, Sakaguchi M, Horikoshi K, Iritani S, Kazamatsuri H, Ikeda K, Tashiro M
A reverse-type sandwich enzyme-linked immunosorbent assay for detecting antibodies to Borna disease virus.
J Clin Microbiol. 1997 Jul;35(7):1661-6.
To investigate whether there is an epidemiological correlation between Borna disease virus (BDV) infection and human neuropsychiatric diseases, we established a reverse-type sandwich enzyme-linked immunosorbent assay (RS-ELISA) for detecting specific antibodies to BDV. In this assay, microplate wells were coated dispersely with BDV p40 antigen, followed by the addition of test samples at a low dilution and then the biotinylated p40. A preformed complex of streptavidin and horseradish peroxidase-conjugated biotin and an enzyme substrate were used to measure the captured biotinylated p40. Theoretically, RS-ELISA should specifically detect anti-BDV antibodies without nonspecific signals; such signals possibly occur in conventional serological assays. Additionally, the RS-ELISA could be applied under the same protocols to test samples from a variety of animals. By using anti-BDV rat and rabbit sera, the assay was standardized so that it had high specificity and sensitivity. When we used the RS-ELISA to determine the presence of anti-BDV antibodies in plasma from 70 patients with chronic schizophrenia as well as 40 healthy individuals in the Tokyo area of Japan, no plasma sample was found to possess specific antibodies to BDV p40, indicating no association between BDV infection and the disease in our testing population. A negative reaction was also shown for the sera that had previously been judged to be seropositive for BDV by an immunofluorescence or immunoblot test. These findings suggested that false-positive cases of infection due to nonspecific reactions may be included in previous seroepidemiological information with regard to BDV. [Abstract]

Kubo K, Fujiyoshi T, Yokoyama MM, Kamei K, Richt JA, Kitze B, Herzog S, Takigawa M, Sonoda S
Lack of association of Borna disease virus and human T-cell leukemia virus type 1 infections with psychiatric disorders among Japanese patients.
Clin Diagn Lab Immunol. 1997 Mar;4(2):189-94.
Borna disease virus (BDV) infection has been suspected to be a possible etiological factor in human psychiatric disorders and recently in chronic fatigue syndrome. Evidence of the correlation of BDV infection with these disorders remained unclear. Kagoshima is known to be one of the major areas in which human T-cell leukemia virus type 1 (HTLV-1) is endemic; this is the first isolated human retrovirus that causes adult T-cell leukemia with neurological symptoms. The present study aimed to clarify whether BDV and HTLV-1 infections are associated with psychiatric disorders among Japanese patients. Subjects were 346 patients with psychiatric disorders (schizophrenia, 179; mood disorder, 123; and others, 44) and 70 healthy controls. Anti-BDV antibodies from plasma samples were screened by the indirect immunofluorescence (IF) method using BDV-infected MDCK cells. Results revealed that only three samples were found to be weakly positive for BDV in the IF assay and seronegative by Western blot (immunoblot) assay. Furthermore, BDV-p24 related RNA in peripheral blood mononuclear cells from 106 of 346 psychiatric patients and 12 or 70 healthy controls by p24-reverse transcription PCR was examined. Two mood disorder patients were positive for BDV-p24 RNA but seronegative. To detect anti-HTLV-1 antibodies the plasma samples were screened by the particle agglutination method and no significant difference in seropositivity for anti-HTLV-1 antibody was found between the patients and healthy controls. These results also suggested that there is a lack of association between BDV and HTLV-1 infections with psychiatric disorders among Japanese patients. [Abstract]

Rodgers-Johnson PE, Hickling FW, Irons A, Johnson BK, Irons-Morgan M, Stone GA, Gibbs CJ
Retroviruses and schizophrenia in Jamaica.
Mol Chem Neuropathol. 1996 May-Aug;28(1-3):237-43.
Reports of an 18-fold higher incidence of schizophrenia among second-generation Afro-Caribbeans, and especially Jamaican migrants in the United Kingdom were soon called "an epidemic of schizophrenia," with the inference that a novel virus, likely to be perinatally transmitted, was a possible etiological agent. This intriguing observation led us to explore a possible link with human T-cell lymphotropic virus type one (HTLV-I), because it is a virus that is endemic in the Caribbean Island, is perinatally transmitted, known to be neuropathogenic, and the cause of a chronic myelopathy (tropical spastic paraparesis/HTLV-I associated myelopathy. We therefore examined inpatients as the Bellevue Mental Hospital, Kingston, Jamaica and did standard erological tests for retroviruses HTLV-I and HTLV-II and HIV-I and HIV-II on 201 inpatients who fulfilled ICD-9 and DSM III-R criteria for schizophrenia. Our results produced important negative data, since the seropositivity rates for HTLV-I, the most likely pathogen, were no greater than the seropositivity range for HTLV-I carriers in this island population, indicating the HTLV-1 and the other retroviruses tested do not play a primary etiological role in Jamaican schizophrenics. [Abstract]

Feenstra A, Kirch DG, Bracha HS, Wyatt RJ
Lack of evidence for a role of T-cell-associated retroviruses as an etiology of schizophrenia.
Biol Psychiatry. 1989 Feb 15;25(4):421-30.
The evidence that schizophrenia may involve infection by a virus (or viruses) has been indirect. The recent discovery, however, of the human retroviruses--human T-cell lymphoma-leukemia virus-I, and II (HTLV-I, -II) and human immunodeficiency virus (HIV)--now also known to affect the central nervous system (CNS), together with the development of new techniques in retrovirology, have made it possible to investigate more directly the role of this class of viruses as an etiology of schizophrenia. In our first effort to screen for the presence of a T-cell lymphotropic virus in schizophrenia, short-term tissue cultures of peripheral lymphocytes from 17 chronic schizophrenic patients and 10 normal controls were established. The cells were cultured in the presence of T-cell growth factor (TCGF, IL-2), and the culture supernatants were tested for the presence of the retroviral enzyme reverse transcriptase. No T-cell-associated reverse transcriptase activity was detected in cultures from patients or normal controls. Therefore, the data do not provide evidence for a role for T-cell lymphotropic retroviruses as an etiology of schizophrenia. [Abstract]

Conejero-Goldberg C, Torrey EF, Yolken RH
Herpesviruses and Toxoplasma gondii in orbital frontal cortex of psychiatric patients.
Schizophr Res. 2003 Mar 1;60(1):65-9.
Herpes simplex virus (HSV), Epstein-Barr virus (EBV), cytomegalovirus (CMV), and human herpesvirus-6 (HHV-6) are viruses capable of establishing latency. All of these infect the CNS and have been detected in human postmortem brains. Toxoplasma gondii is a protozoan organism which can reactivate in the brains of previously infected immunocompromised individuals. To screen for the presence of herpesviruses and T. gondii in postmortem orbital frontal brain samples from patients with schizophrenia, affective disorders, and controls, we used nested-polymerase chain reaction (n-PCR)/sequencing. We identified HHV-6B sequences in 2/51 postmortem brain samples but no sequences from other herpesviruses. We did not detect sequences of T. gondii in the postmortem brains. Additional studies including ones directed at the sensitive detection of viral nucleic acids in multiple brain regions should be directed at confirming or excluding a role for viruses and protozoa in the etiology of these disorders. [Abstract]

Altamura AC, Bassetti R, Bocchio L, Santini A, Mundo E
Season of birth and inflammatory response system in schizophrenia.
Prog Neuropsychopharmacol Biol Psychiatry. 2003 Aug;27(5):879-80.
Infective agents (e.g., viruses) together with functional alterations of the immune system have been hypothesized to be implicated in the multifactorial pathogenesis of schizophrenia. The viral hypothesis of schizophrenia has been supported by the observation of birth peaks in winter seasons, prenatal exposure to virus epidemics and specific geographic patterns. On the other hand, not all the data published have shown consistent results supporting the immune hypothesis. Thus, it is likely that immune response factors may play a role in the pathogenesis of the disease only in specific subgroups of patients. The aim of the study was to investigate for the presence of differences of IL-6, IL-6R, gp130 and CC16 among four groups of chronic schizophrenic patients categorized according to the season of birth. We hypothesized that patients born in winter and spring would have had increased values of these cytokines. No significant differences were found among the four groups in any of the measures considered. These preliminary results appear to exclude a major role of the season of birth in determining reported interleukins system alterations in chronic schizophrenia. [Abstract]

Brown JS
Geographic correlation of schizophrenia to ticks and tick-borne encephalitis.
Schizophr Bull. 1994;20(4):755-75.
Schizophrenia prevalence in the United States is highest in urbanized Northeastern, Northwestern, and Great Lakes States. The viral theory of schizophrenia attributes this distribution to enhanced susceptibility to viral infections in crowded, urban areas. Such infections during fetal or perinatal development are hypothesized to result in the eventual onset of schizophrenia. This study attempts to identify which viral infections have a similar geographical distribution to schizophrenia. Examination of the geographical distribution of infectious diseases in the United States reveals that the spreading foci of Lyme disease and its primary vectors, Ixodid ticks, correlate significantly with high schizophrenia rate areas. Ixodid ticks are vectors in North America and throughout the world of tick-borne encephalitis (TBE). The international distribution of TBE is shown to be concentrated in countries where the highest rates of schizophrenia are found: Croatia, Norway, Finland, Germany, Ireland, and others. The geographical specificity of this correlation and the plausibility of a tick-associated or TBE theory of schizophrenia are discussed. [Abstract]

Brown JS
A novel mechanism to explain protein abnormalities in schizophrenia based on the flavivirus resistance gene.
Mol Psychiatry. 2001 Nov;6(6):701-11.
The geographical distribution of schizophrenia was previously shown to correlate with the global distribution of tick-borne flaviviruses. The correlation suggests a natural resistance gene to flaviviruses could be involved in schizophrenia. The flavivirus resistance gene, Flv, a gene found in wild mice and certain in-bred strains, confers resistance to flaviviruses through the interaction of cellular proteins with the flaviviral 3' untranslated regions (UTRs). Although the sequence and product of Flv are unknown, translation elongation factor alpha-1 (EF-1) is a protein known to interact with the 3' UTR flavivirus RNA, forming some complexes with long half-lives that inhibit RNA growth. A study was performed to assess the homology between flaviviral UTRs, subunits of EF-1, and selected proteins reported as abnormal in schizophrenia. The UTRs of four flaviviruses with wide geographical and phylogenic distribution were manually translated. Using the National Biomedical Research Foundation protein databank, the amino acid sequences were correlated with the amino acid sequences of selected proteins. The amino acid sequences of the EF-1 subunits were then correlated with the same proteins. Similar amino acid correlations between the proteins, EF-1 subunits and viral UTRs suggest that translational pathophysiology resulting from the product of Flv can be postulated as the cause of protein abnormalities observed in schizophrenia. [Abstract]

Borrell J, Vela JM, Arévalo-Martin A, Molina-Holgado E, Guaza C
Prenatal immune challenge disrupts sensorimotor gating in adult rats. Implications for the etiopathogenesis of schizophrenia.
Neuropsychopharmacology. 2002 Feb;26(2):204-15.
Increasing evidence associates schizophrenia with prenatal exposure to infection. Impaired ability to "gate out" sensory and cognitive information is considered to be a central feature of schizophrenia and is manifested, among others, in disrupted prepulse inhibition (PPI) of the acoustic startle reflex. We analyzed the effect of a prenatal immune challenge- peripheral administration of bacterial endotoxin lipopolysaccharide (LPS) to pregnant female rats-upon PPI and immune function in adult offspring. Prenatal LPS treatment disrupted PPI which was reversed by antipsychotics. Serum levels of interleukin-2 and interleukin-6 were increased. In addition, histopathological features in brain areas related with PPI circuitry were observed. These results illustrate the critical influence of prenatal immune events upon adult CNS functioning in association with the putative role of the immune system in the etiopathogenesis of schizophrenia. [Abstract]

Printz DJ, Strauss DH, Goetz R, Sadiq S, Malaspina D, Krolewski J, Gorman JM
Elevation of CD5+ B lymphocytes in schizophrenia.
Biol Psychiatry. 1999 Jul 1;46(1):110-8.
BACKGROUND: A variety of immunologic alterations have been observed in patients with schizophrenia. These findings have lent support to theories that autoimmune mechanisms may be important in some patients with the illness. The CD5+ B lymphocyte, a B-cell subset associated with autoimmune disease, has been the subject of two previously published studies yielding disparate results. METHODS: In this study, we used immunofluorescent flow cytometry to measure CD5+ B cells, total B and T cells, and CD4 and CD8 subsets in patients with schizophrenia and in normal control subjects. RESULTS: A significantly higher percentage of patients with schizophrenia, relative to normal control subjects, exhibited an elevated level of CD5+ B cells (27.6% vs 6.7%). Antipsychotic withdrawal had no effect on CD5+ B-cell levels, suggesting that medication effects were not the cause of this difference. No other studied lymphocyte subsets differed between the two groups. CONCLUSIONS: A subset of patients with schizophrenia have elevated levels of CD5+ B cells. This finding replicates an earlier study by another group and provides further evidence suggestive of autoimmune manifestations in schizophrenia. [Abstract]

McAllister CG, Rapaport MH, Pickar D, Podruchny TA, Christison G, Alphs LD, Paul SM
Increased numbers of CD5+ B lymphocytes in schizophrenic patients.
Arch Gen Psychiatry. 1989 Oct;46(10):890-4.
Autoimmune mechanisms have been postulated to play a role in the pathogenesis of schizophrenia. Recently, increased numbers of B lymphocytes expressing the CD5 (Leu-1) surface antigen have been observed in patients with certain autoimmune diseases. In the present study, approximately 30% of schizophrenic patients (11/34) were found by cytofluorometric methods to have similarly increased levels of circulating CD5+ B cells compared with 6% (2/33) of healthy individuals and 5% (1/20) of patients with bipolar affective disorder. In schizophrenic patients with a "high" CD5+ B-cell phenotype, the percentage of B cells expressing the CD5 surface marker (mean +/- SEM, 52.4% +/- 3.5%) was comparable to that reported for patients with rheumatoid arthritis and significantly greater than that reported for patients with bipolar affective disorder (25.7% +/- 2.5%) and healthy controls (31.0% +/- 1.8%). Schizophrenic patients with high levels of CD5+ B cells had increased numbers of total B cells compared with control subjects and patients with low levels of CD5+ B cells. An elevation in CD5+ B cells may delineate a subgroup of schizophrenic patients whose disease has an underlying autoimmune and/or genetic cause. [Abstract]

Ganguli R, Rabin BS
CD5 positive B lymphocytes in schizophrenia: no alteration in numbers or percentage as compared with control subjects.
Psychiatry Res. 1993 Jul;48(1):69-78.
Some patients with autoimmune disease have an elevation of the B lymphocyte population bearing the CD5 marker. In an attempt to replicate an earlier report of elevated CD5+ B cells in schizophrenic patients, lymphocytes were phenotyped in 116 patients with schizophrenia and 166 control subjects. The CD5+ B lymphocyte population was not elevated in medicated or never-medicated patients as compared with control subjects of similar age, race, gender, or social class. CD5+ B cells were also not elevated in patients who had circulating autoantibodies. The CD5+ B lymphocyte population was significantly elevated in African-American control subjects and patients in comparison with that in Caucasian control subjects and patients. Thus, although other immune alterations characterized a subset of patients with schizophrenia, an elevation of the CD5+ B lymphocyte population was not found in this study. [Abstract]

Galinowski A, Barbouche R, Truffinet P, Louzir H, Poirier MF, Bouvet O, Loo H, Avrameas S
Natural autoantibodies in schizophrenia.
Acta Psychiatr Scand. 1992 Mar;85(3):240-2.
Autoantibodies reacting with cell constituents other than antinuclear antibodies have seldom been reported in the literature on schizophrenia. Serum of 41 DSM-III-R schizophrenic patients was examined for the presence of various autoantibodies and compared with that of healthy volunteers (n = 10) and hospitalized controls. Titers of IgG, IgA and IgM autoantibodies directed against actin, tubulin, myosin, DNA, thyroglobulin, elastin, albumin, DNA and trinitrophenyl groups were etermined using enzyme immunoassay. IgG and IgA titers were significantly decreased in schizophrenic patients. These results contrast with those obtained with various other autoimmune and nonautoimmune diseases in which titers are either unchanged or increased. A significant increase of various autoantibody levels was observed in the paranoid subgroup of schizophrenics compared with the disorganized subgroup. These autoantibodies possess characteristics similar to those of natural autoantibodies, which seem to play several biological roles. [Abstract]

Sane AS, Chawla MS, Chokshi SA, Mathur V, Barad DP, Shah VC, Patel MJ
Serum immunoglobulin status of psychiatric in-patients.
Panminerva Med. 1990 Apr-Jun;32(2):88-91.
In view of the fact that substantial evidence today links psyche, brain, stress and immune system, he serum immunoglobulin (viz. IgG, IgA, IgM) levels in 40 patients with psychiatric disorders (viz. Schizophrenia, Affective disorder and generalized Anxiety disorders) have been investigated. With the exception of IgA, all psychiatric patients had significantly elevated IgG, IgM levels (p less than 0.001) when compared with healthy controls. Surprisingly these immunoglobulin levels irrespective of prevalent psychiatric disorder were almost similar to those of the hospitalized surgical patients pre-operatively (preferable controls), suggestive of no direct linear causal relationship between the psychiatric disorder and serum immunoglobulin levels. Factors affecting immunoglobulins have been discussed. Considering a probable viral association in Schizophrenia it is felt that simultaneous monitoring of viruses (affecting the nervous system) in the form of antigen/antibodies may be more informative. [Abstract]

Kirch DG, Alexander RC, Suddath RL, Papadopoulos NM, Kaufmann CA, Daniel DG, Wyatt RJ
Blood-CSF barrier permeability and central nervous system immunoglobulin G in schizophrenia.
J Neural Transm Gen Sect. 1992;89(3):219-32.
The ratio of albumin in cerebrospinal fluid (CSF) to serum may serve as an index of the integrity of the blood-CSF barrier, with increases in this ratio indicating increased permeability. The ratio of immunoglobulin G (IgG) in CSF to serum (divided by the albumin ratio to correct for variance in blood-CSF permeability) represents an index of the endogenous production of IgG in the central nervous system (CNS), with increases reflecting a possible infectious and/or autoimmune process stimulating central IgG synthesis. We analyzed simultaneously collected CSF and serum samples from 46 schizophrenic subjects, 8 of whom were studied both on and off neuroleptic treatment, and samples from 20 normal controls. The data indicated increases in CSF/serum albumin ratios or CSF/serum IgG indices in 22% and 20%, respectively, of the schizophrenic patients. Only 3 patients showed elevations in both indices. Comparison of values on and off neuroleptics indicated no significant effect of neuroleptics on these indices. [Abstract]

Kokai M, Morita Y, Fukuda H, Hatotani N
Immunophenotypic studies on atypical lymphocytes in psychiatric patients.
Psychiatry Res. 1998 Feb 9;77(2):105-12.
By using phase-contrast microscopy combined with a fluorescent staining technique, the frequency of blast-type atypical lymphocytes (BTALs) appearing in peripheral blood and the phenotypic expression of their surface antigens were studied in 24 patients with schizophrenia, 16 with mood disorder and 14 healthy controls. BTALs were classified as being stimulated or activated cells, morphologically characterized by their large size, dark cytoplasm, a hollow perinuclear containing a few granules and finely dispersed chromatin structures with a few evident nucleoli. A significantly higher number of BTALs were found in the schizophrenic patients compared with healthy control subjects or patients with mood disorder. Further, there was a significant difference in the frequency of BTALs between patients with mood disorder and healthy control subjects. No significant difference in the frequency of BTALs was found between the schizophrenic patients with and without medication. Immunostaining of BTALs revealed that these cells consisted of B, T and non-B, non-T cell subpopulations. Contrary to our expectations, the T cell was only one third of the BTAL population. HLA-DR and CD38 were expressed on most BTALs (> 70%), while CD25, an early activation marker of T cells was rarely found on BTALs (< 0.3%). The differences in activated lymphocyte populations which appeared as morphologically atypical in the circulation among some psychiatric patients and infectious or autoimmune diseases are discussed. This is the first report on populations of BTALs. [Abstract]

Cannon TD, Rosso IM, Bearden CE, Sanchez LE, Hadley T
A prospective cohort study of neurodevelopmental processes in the genesis and epigenesis of schizophrenia.
Dev Psychopathol. 1999;11(3):467-85.
A number of lines of evidence converge in implicating neurodevelopmental processes in the etiology and epigenesis of schizophrenia. In this study we used a prospective, longitudinal design to examine whether adverse obstetric experiences predict schizophrenia and whether there is a deviant functional-developmental trajectory during the first 7 years of life among individuals who manifest schizophrenia as adults. The 9,236 members of the Philadelphia cohort of the National Collaborative Perinatal Project were screened for mental health service utilization in adulthood, and chart reviews were performed to establish diagnoses according to DSM-IV criteria. The risk for schizophrenia increased linearly with the number of hypoxia-associated obstetric complications but was unrelated to maternal infection during pregnancy or fetal growth retardation. Preschizophrenic cases (and their unaffected siblings who were also cohort members) manifested cognitive impairment, abnormal involuntary movements and coordination deficits, and poor social adjustment during childhood. There was no evidence of intraindividual decline in any domain, but preschizophrenic cases did show deviance on an increasing number of functional indicators with age. Together, these findings suggest that both genetic and obstetric factors participate in creating a neural diathesis to schizophrenia, the phenotypic expressions of which are age dependent, probably reflecting the maturational status of a number of interconnected brain systems. [Abstract]

Boog G
Obstetrical complications and subsequent schizophrenia in adolescent and young adult offsprings: is there a relationship?
Eur J Obstet Gynecol Reprod Biol. 2004 Jun 15;114(2):130-6.
Schizophrenia is a psychiatric disease affecting around 1% of the population, the negative signs of which are correlated with inactivity of the prefrontal dorsolateral cortex, while an increased, more deeply localized, activity in the mesolimbic pathway may explain the positive signs. Several events occurring during pregnancy are likely to be involved in its genesis: hormonal supplementation by diethylstilbestrol, severe maternal denutrition, exposure to influenza virus, repeated psychological stress. From multicentric studies and meta-analyses in the psychiatric literature, the risk of schizophrenia appears to be multiplied by two if pregnancy is complicated, mainly by diabetes, Rhesus incompatibility, bleeding, preeclampsia, premature rupture of membranes and preterm birth. When delivery is linked to an abnormal presentation or happens via a caesarean birth for acute foetal distress, the time when the first signs of psychosis appear seems to be earlier in adolescence or in early adulthood. Cerebral imaging of schizophrenic patients shows ventriculomegaly and gray matter reduction, mainly in hippocampal volumes and in the dorsolateral prefrontal cortex. Similar alterations in the neuronal pathways have been experimentally reproduced in rats after repeated prenatal stress and perinatal hypoxia. A region on the distal portion of chromosome 1 has shown evidence for linkage to schizophrenia. Therefore, a two factor model seems to be able to explain the onset of schizophrenia in which obstetrical complications may interact with a genetic liability and in which the consequences of hypoxic events may lie on a continuum ranging from cerebral palsy in some children to subtle cognitive and behavioural disturbances in others. [Abstract]

Jacobsen LK, Mittleman BB, Kumra S, Lenane MC, Barracchini KC, Adams S, Simonis T, Lee PR, Long RT, Sharp W, Sidransky E, Ginns EI, Rapoport JL
HLA antigens in childhood onset schizophrenia.
Psychiatry Res. 1998 May 8;78(3):123-32.
Evidence of immune system abnormalities in adult schizophrenia has prompted examination of the human leukocyte antigen (HLA) system. Childhood onset schizophrenia offers a unique opportunity to test neurodevelopmental hypotheses of schizophrenia, including those which implicate components of the immune system. In the present study, class I and II HLA antigens were typed using sequence-specific primers and the polymerase chain reaction in 28 childhood onset schizophrenics and 51 ethnically matched healthy subjects. Groups were compared for frequencies of HLA antigens reported to be associated with schizophrenia and/or autoimmune disorders. We hypothesized that antigen frequencies would differ between schizophrenic and healthy children, suggesting that some dimension of the neurodevelopmental disturbance experienced by these children may be mediated by subtle abnormalities of immune function. There were no significant differences between schizophrenic and healthy subjects in the frequency of any antigen tested. These findings do not support HLA-associated pathology in childhood onset schizophrenia. [Abstract]

Schroers R, Nöthen MM, Rietschel M, Albus M, Maier W, Schwab S, Wildenauer D, Fimmers R, Propping P, Dewald G
Investigation of complement C4B deficiency in schizophrenia.
Hum Hered. 1997 Sep-Oct;47(5):279-82.
Several lines of evidence suggest that autoimmune mechanisms might contribute to the development of schizophrenia. Important factors involved in immune responses in man include the human leukocyte antigens and components of the complement system. In the present study we attempted to confirm a positive association between a homozygous deficiency in complement factor C4B and schizophrenia as previously reported. We also determined parental genotypes in a subset of our schizophrenic patients to test the hypothesis of a genetic mechanism depending on the mother's genotype. C4B deficiency was found in similar frequency among patients (n = 176) and controls (n = 145). There was also no increased frequency of C4B deficiency in the mothers of schizophrenic patients. Our study does not support a widespread or consistent association between a deficiency in complement component C4B and schizophrenia. [Abstract]

Muck-Jørgensen P, Mors O, Mortensen PB, Ewald H
The schizophrenic patient in the somatic hospital.
Acta Psychiatr Scand Suppl. 2000;(407):96-9.
OBJECTIVE: There is an increased risk in schizophrenia for premature death from illnesses in almost all organic systems. The present study analyses the Rate Ratio (RR) for schizophrenic patients' admissions to somatic departments in Denmark. METHOD: 20000 schizophrenic patients were identified in the Danish Psychiatric Central Register and 200000 sex- and age-matched controls were identified in the Danish Central Person Register. Both groups were searched for in the Danish National Patient Register in which admissions to all somatic departments are registered. Pulmonary and cardiovascular diseases are used as examples. RESULTS: RR is increased for several diseases, especially infectious, up to a maximum of RR = 4.15 for severe heart failures and decreased to as low as RR = 0.35 for atherosclerotic diseases of the brain vessels. CONCLUSION: It seems that individuals with schizophrenia are rarely treated for their physical illness in its early, less severe phases, but more likely in its acute phases when the disease is severe, life-threatening or painful. [Abstract]







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Recent Autoimmunity and Infection in Schizophrenia Research

1) Ferentinos P, Dikeos D
Genetic correlates of medical comorbidity associated with schizophrenia and treatment with antipsychotics.
Curr Opin Psychiatry. 2012 Jul 25;
PURPOSE OF REVIEW: High comorbidity rates for various medical conditions have been documented in schizophrenia, being explained by factors either inherent to the disease or associated with antipsychotic treatment. The aim of this study is to review the genetic factors contributing to medical comorbidity in schizophrenia. RECENT FINDINGS: Based on clinical genetic studies in schizophrenia, comorbid impaired glucose tolerance/type 2 diabetes mellitus, most autoimmune disorders and cardiac autonomic dysregulation have the strongest evidence for familial predisposition. Similarly, of antipsychotic-induced adverse drug reactions, tardive dyskinesia, neuroleptic malignant syndrome, and antipsychotic-induced weight gain have some evidence for familial clustering. On the molecular genetic level, schizophrenia seems to share specific genes with type 2 diabetes mellitus and with autoimmune disorders. Various genes have been proposed to account for the reduced incidence of rheumatoid arthritis and cancer in schizophrenic patients and their relatives. Many pharmacogenetic association studies have pinpointed numerous, though often contradictory or poorly replicated, genes of modest effect size for tardive dyskinesia, neuroleptic malignant syndrome, clozapine-induced agranulocytosis, hyperprolactinaemia, antipsychotic-induced weight gain, and antipsychotic-induced QT prolongation. SUMMARY: Unravelling the genetic underpinnings of medical comorbidity associated with schizophrenia and its treatment is expected to highlight new pathogenetic pathways in both schizophrenia and comorbid medical conditions, and introduce personalized treatment strategies for schizophrenia patients. [PubMed Citation] [Order full text from Infotrieve]

2) Garay PA, Hsiao EY, Patterson PH, Kimberley McAllister A
Maternal immune activation causes age- and region-specific changes in brain cytokines in offspring throughout development.
Brain Behav Immun. 2012 Jul 25;
Maternal infection is a risk factor for autism spectrum disorder (ASD) and schizophrenia (SZ). Indeed, modeling this risk factor in mice through maternal immune activation (MIA) causes ASD- and SZ-like neuropathologies and behaviors in the offspring. Although MIA upregulates pro-inflammatory cytokines in the fetal brain, whether MIA leads to long-lasting changes in brain cytokines during postnatal development remains unknown. Here, we tested this possibility by measuring protein levels of 23 cytokines in the blood and three brain regions from offspring of poly(I:C)- and saline-injected mice at five postnatal ages using multiplex arrays. Most cytokines examined are present in sera and brains throughout development. MIA induces changes in the levels of many cytokines in the brains and sera of offspring in a region- and age-specific manner. These MIA-induced changes follow a few, unexpected and distinct patterns. In frontal and cingulate cortices, several, mostly pro-inflammatory, cytokines are elevated at birth, followed by decreases during periods of synaptogenesis and plasticity, and increases again in the adult. Cytokines are also altered in postnatal hippocampus, but in a pattern distinct from the other regions. The MIA-induced changes in brain cytokines do not correlate with changes in serum cytokines from the same animals. Finally, these MIA-induced cytokine changes are not accompanied by breaches in the blood-brain barrier, immune cell infiltration or increases in microglial density. Together, these data indicate that MIA leads to long-lasting, region-specific changes in brain cytokines in offspring-similar to those reported for ASD and SZ-that may alter CNS development and behavior. [PubMed Citation] [Order full text from Infotrieve]

3) Garbett KA, Hsiao EY, Kálmán S, Patterson PH, Mirnics K
Effects of maternal immune activation on gene expression patterns in the fetal brain.
Transl Psychiatry. 2012 Feb 21;2:e98.
We are exploring the mechanisms underlying how maternal infection increases the risk for schizophrenia and autism in the offspring. Several mouse models of maternal immune activation (MIA) were used to examine the immediate effects of MIA induced by influenza virus, poly(I:C) and interleukin IL-6 on the fetal brain transcriptome. Our results indicate that all three MIA treatments lead to strong and common gene expression changes in the embryonic brain. Most notably, there is an acute and transient upregulation of the ?, ? and ? crystallin gene family. Furthermore, levels of crystallin gene expression are correlated with the severity of MIA as assessed by placental weight. The overall gene expression changes suggest that the response to MIA is a neuroprotective attempt by the developing brain to counteract environmental stress, but at a cost of disrupting typical neuronal differentiation and axonal growth. We propose that this cascade of events might parallel the mechanisms by which environmental insults contribute to the risk of neurodevelopmental disorders such as schizophrenia and autism. [PubMed Citation] [Order full text from Infotrieve]

4) Røge R, Møller BK, Andersen CR, Correll CU, Nielsen J
Immunomodulatory effects of clozapine and their clinical implications: What have we learned so far?
Schizophr Res. 2012 Jul 23;
Clozapine remains the drug of choice for treatment resistant schizophrenia, but is associated with potentially life threatening side effects, including agranulocytosis and myocarditis. Immunological mechanisms may be involved in the development of these side effects or in the unique antipsychotic efficacy in subgroups of schizophrenia patients. This systematic review presents the immunomodulatory effects of clozapine from human in vitro and in vivo studies and relates these findings to the developments of adverse and therapeutic effects of clozapine. Several studies confirm the immunomodulatory actions of clozapine, but only few studies investigated their relationship to the unique adverse and therapeutic effects of clozapine. During the first month of clozapine treatment, up to 50% of patients develop fever and flu like symptoms, which is seemingly driven by increased cytokines. Within the same time period, the risk of side-effects with a suspected immunological mechanism peaks. Patients developing fever during the first weeks of treatment should have a thorough physical examination, and measurements of white blood cell count, absolute neutrophil count, ECG, C-reactive protein, creatinine kinase, and troponin to exclude infection, agranulocytosis, myocarditis and neuroleptic malignant syndrome. To what degree the unique antipsychotic efficacy of clozapine in subgroups of schizophrenia patients is related to its immunomodulatory effects has not been studied. Research relating the immunomodulatory actions of clozapine and its early markers to clinically relevant adverse and therapeutic outcomes is hoped to provide new leads for the understanding of the pathophysiology of schizophrenia and aid the development of novel treatment targets. [PubMed Citation] [Order full text from Infotrieve]

5) Benros ME, Mortensen PB, Eaton WW
Autoimmune diseases and infections as risk factors for schizophrenia.
Ann N Y Acad Sci. 2012 Jul;1262(1):56-66.
Immunological hypotheses have become increasingly prominent when studying the etiology of schizophrenia. Autoimmune diseases, and especially the number of infections requiring hospitalization, have been identified as significant risk factors for schizophrenia in a dose-response relationship, which seem compatible with an immunological hypothesis for subgroups of patients with schizophrenia. Inflammation and infections may affect the brain through many different pathways that are not necessarily mutually exclusive and can possibly increase the risk of schizophrenia in vulnerable individuals. However, the findings could also be an epiphenomenon and not causal, due to, for instance, common genetic vulnerability, which could be supported by the observations of an increased prevalence of autoimmune diseases and infections in parents of patients with schizophrenia. Nevertheless, autoimmune diseases and infections should be considered in the treatment of individuals with schizophrenia symptoms, and further research is needed of the immune system's possible contributing pathogenic factors in the etiology of schizophrenia. [PubMed Citation] [Order full text from Infotrieve]

6) Blomström A, Karlsson H, Wicks S, Yang S, Yolken RH, Dalman C
Maternal antibodies to infectious agents and risk for non-affective psychoses in the offspring-a matched case-control study.
Schizophr Res. 2012 Jul 20;
BACKGROUND: An increasing number of studies suggest that certain maternal infections are associated with non-affective psychoses in the offspring. Here we investigated if maternal exposure to Toxoplasma gondii, cytomegalovirus (CMV), herpes simplex virus type 1 (HSV-1) or type 2 (HSV-2) prior to delivery was associated with future diagnosis of schizophrenia or other non-affective psychoses in the offspring. METHODS: This case-control study included 198 individuals born in Sweden 1975-85, diagnosed with schizophrenia (ICD-10, F20) and other non-affective psychoses (ICD-10, F21-29) as in- or outpatients, and 524 matched controls. Specific immunoglobulin G (IgG) levels in archived neonatal dried blood samples from these individuals were determined by immunoassays. Reference levels were determined by prevalences among pregnant women in Sweden 1975-85. Odds ratios (OR) for schizophrenia and other non-affective psychoses were calculated, considering maternal and gestational factors as covariates. RESULTS: Levels of IgG directed at T. gondii corresponding to maternal exposure was associated with subsequent schizophrenia (OR=2.1, 95% CI 1.0-4.5) as were levels of IgG directed at CMV (OR=2.2, 95% CI 1.0-5.1) but not at HSV-1 or -2. There were even stronger associations with higher levels of T. gondii or CMV antibodies. There were no associations between any of the infectious agents and other non-affective psychoses. CONCLUSIONS: This study supports findings of maternal exposure to T. gondii and schizophrenia risk in offspring, and extends the risk to also include maternal exposure to CMV. Future studies should confirm the association with CMV exposure and identify mechanisms underlying these associations. [PubMed Citation] [Order full text from Infotrieve]

7) Connor CM, Dincer A, Straubhaar J, Galler JR, Houston IB, Akbarian S
Maternal immune activation alters behavior in adult offspring, with subtle changes in the cortical transcriptome and epigenome.
Schizophr Res. 2012 Jul 15;
Maternal immune activation during prenatal development, including treatment with the viral RNA mimic, polyriboinosinic-polyribocytidilic acid (poly IC), serves as a widely used animal model to induce behavioral deficits reminiscent of schizophrenia and related disease. Here, we report that massive cytokine activation after a single dose of poly IC in the prenatal period is associated with lasting working memory deficits in adult offspring. To explore whether dysregulated gene expression in cerebral cortex, contributes to cognitive dysfunction, we profiled the cortical transcriptome, and in addition, mapped the genome-wide distribution of trimethylated histone H3-lysine 4 (H3K4me3), an epigenetic mark sharply regulated at the 5' end of transcriptional units. However, deep sequencing-based H3K4me3 mapping and mRNA profiling by microarray did not reveal significant alterations in mature cerebral cortex after poly IC exposure at embryonic days E17.5 or E12.5. At a small set of genes (including suppressor of cytokine signaling Socs3), H3K4me3 was sensitive to activation of cytokine signaling in primary cultures from fetal forebrain but adult cortex of saline- and poly IC-exposed mice did not show significant differences. A limited set of transcription start sites (TSS), including Disrupted-in-Schizophrenia 1 (Disc1), a schizophrenia risk gene often implicated in gene-environment interaction models, showed altered H3K4me3 after prenatal poly IC but none of these differences survived after correcting for multiple comparisons. We conclude that prenatal poly IC is associated with cognitive deficits later in life, but without robust alterations in epigenetic regulation of gene expression in the cerebral cortex. [PubMed Citation] [Order full text from Infotrieve]

8) Petry NM, Rash CJ, Byrne S, Ashraf S, White WB
Financial Reinforcers for Improving Medication Adherence: Findings from a Meta-analysis.
Am J Med. 2012 Jul 14;
BACKGROUND: Increasingly, financial reinforcement interventions based on behavioral economic principles are being applied in health care settings, and this study examined the use of financial reinforcers for enhancing adherence to medications. METHODS: Electronic databases and bibliographies of relevant references were searched, and a meta-analysis of identified trials was conducted. The variability in effect size and the impact of potential moderators (study design, duration of intervention, magnitude of reinforcement, and frequency of reinforcement) on effect size were examined. RESULTS: Fifteen randomized studies and 6 nonrandomized studies examined the efficacy of financial reinforcement interventions for medication adherence. Financial reinforcers were applied for adherence to medications for tuberculosis, substance abuse, human immunodeficiency virus, hepatitis, schizophrenia, and stroke prevention. Reinforcement interventions significantly improved adherence relative to control conditions with an overall effect size of 0.77 (95% confidence interval, 0.70-0.84; P<.001). Nonrandomized studies had a larger average effect size than randomized studies, but the effect size of randomized studies remained significant at 0.44 (95% confidence interval, 0.35-0.53; P<.001). Interventions that were longer in duration, provided an average reinforcement of $50 or more per week, and reinforced patients at least weekly resulted in larger effect sizes than those that were shorter, provided lower reinforcers, and reinforced patients less frequently. CONCLUSION: These results demonstrate the efficacy of medication adherence interventions and underscore principles that should be considered in designing future adherence interventions. Financial reinforcement interventions hold potential for improving medication adherence and may lead to benefits for both patients and society. [PubMed Citation] [Order full text from Infotrieve]

9) Anderson G, Maes M
Schizophrenia: Linking prenatal infection to cytokines, the tryptophan catabolite (TRYCAT) pathway, NMDA receptor hypofunction, neurodevelopment and neuroprogression.
Prog Neuropsychopharmacol Biol Psychiatry. 2012 Jul 16;
In 1995, the macrophage-T lymphocyte theory of schizophrenia (Smith and Maes, 1995) considered that activated immuno-inflammatory pathways may account for the higher neurodevelopmental pathology linked with gestational infections through the detrimental effects of activated microglia, oxidative and nitrosative stress (O&NS), cytokine-induced activation of the tryptophan catabolite (TRYCAT) pathway and consequent modulation of the N-methyl d-aspartate receptor (NMDAr) and glutamate production. The aim of the present paper is to review the current state-of-the art regarding the role of the above pathways in schizophrenia. Accumulating data suggest a powerful role for prenatal infection, both viral and microbial, in driving an early developmental etiology to schizophrenia. Models of prenatal rodent infection show maintained activation of immuno-inflammatory pathways coupled to increased microglia activation. The ensuing activation of immuno-inflammatory pathways in schizophrenia may activate the TRYCAT pathway, including increased kynurenic acid (KA) and neurotoxic TRYCATs. Increased KA, via the inhibition of the ?7 nicotinic acetylcholine receptor, lowers gamma-amino-butyric-acid (GABA)ergic post-synaptic current, contributing to dysregulated glutamatergic activity. Hypofunctioning of the NMDAr on GABAergic interneurons will contribute to glutamatergic dysregulation. Many susceptibility genes for schizophrenia are predominantly expressed in early development and will interact with these early developmental driven changes in the immuno-inflammatory and TRYCAT pathways. Maternal infection and subsequent immuno-inflammatory responses are additionally associated with O&NS, including lowered antioxidants such as glutathione. This will contribute to alterations in neurogenesis and myelination. In such a scenario a) a genetic or epigenetic potentiation of immuno-inflammatory pathways may constitute a double hit on their own, stimulating wider immuno-inflammatory responses and thus potentiating the TRYCAT pathway and subsequent NMDAr dysfunction and neuroprogression; and b) antipsychotic-induced changes in immuno-inflammatory, TRYCAT and O&NS pathways would modulate the CNS glia-neuronal interactions that determine synaptic plasticity as well as myelin generation and maintenance. [PubMed Citation] [Order full text from Infotrieve]

10) Zheng W, Wang H, Zeng Z, Lin J, Little PJ, Srivastava LK, Quirion R
The possible role of the Akt signaling pathway in schizophrenia.
Brain Res. 2012 Jul 4;
Serine/threonine protein kinase v-akt murine thymoma viral oncogene homolog (Akt) is one of the survival kinases with multiple biological functions in the brain and throughout the body. Schizophrenia is one of the most devastating psychiatric disorders. Accumulating evidence has indicated the involvement of the Akt signaling pathway in the pathogenesis of this disorder. Genetic linkage and association studies have identified Akt-1 as a candidate susceptibility gene related for schizophrenia. The level of Akt-1 protein and its kinase activity decreased significantly both in white blood cells from schizophrenic patients and in postmortem brain tissue of schizophrenic patients. Consistent with these findings, alterations in the upstream and downstream pathways of Akt have also been found in many psychiatric disorders. Furthermore, both typical and atypical antipsychotic drugs modify the Akt signaling pathway in a variety of conditions relative to schizophrenia. In addition as a survival kinase, Akt participates in neurodevelopment, synaptic plasticity, protein synthesis and neurotransmission in the central nervous system. It is thought that reduced activity of phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway could at least partially explain the cognitive impairment, synaptic morphologic abnormality, neuronal atrophy and dysfunction of neurotransmitter signaling in schizophrenia. In addition, reduced levels of Akt may increase the effects of risk factors on neurodevelopment, attenuate the effects of growth factors on neurodevelopment and reduce the response of patients to antipsychotic agents. More recently, the role of Akt signaling in the functions of schizophrenia susceptibility genes such as disrupted-in-schizophrenia 1 (DISC-1), neuregulin-1 (NRG-1) and dysbindin-1 has been reported. Thus, Akt deficiency may create a context permissive for the expression of risk-gene effects in neuronal morphology and function. This paper reviews the role of Akt in the pathophysiology of schizophrenia and as a potential therapeutic strategy targeting Akt. [PubMed Citation] [Order full text from Infotrieve]

11) Masvidal Aliberch RM, Ortigosa Gómez S, Baraza Mendoza MC, Garcia-Algar O
[Vitamin D: pathophysiology and clinical applicability in paediatrics.]
An Pediatr (Barc). 2012 Jul 3;
Vitamin D has always been associated with calcium -phosphate metabolism, but vitamin D receptors or its metabolites have been found in different body cells, indicating a possible involvement in other physiological mechanisms. Vitamin D deficiency has been associated with an increased risk of infections, autoimmune diseases, diabetes, metabolic syndrome, obesity, asthma and certain neurological diseases such as schizophrenia. Currently there are different techniques for measuring 25 (OH) cholecalciferol in blood, but the results are variable and controversial. It is important to achieve standardization of these techniques to be able to compare the results obtained in different studies. Normal physiological vitamin D levels have not yet been established, but they must be higher than 20 ng/ml (50 nmol/l) in order to perform it physiological function. It is still under discussion on how to achieve these minimum levels. Since the main source of vitamin D is sunlight, we should look for strategies that do not contradict the messages of prevention of skin cancer. In recent years, recommendations for vitamin D intake have changed, involving prophylactic activities carried out in Primary Care. This manuscript reviews the physiology, actions, laboratory determination, desirable levels, and vitamin D intake recommendations, and it highlights many questions raised by new research. [PubMed Citation] [Order full text from Infotrieve]

12) Bechter K
Updating the mild encephalitis hypothesis of schizophrenia.
Prog Neuropsychopharmacol Biol Psychiatry. 2012 Jul 3;
Schizophrenia seems to be a heterogeneous disorder. Emerging evidence indicates that low level neuroinflammation (LLNI) may not occur infrequently. Many infectious agents with low overall pathogenicity are risk factors for psychoses including schizophrenia and for autoimmune disorders. According to the mild encephalitis (ME) hypothesis, LLNI represents the core pathogenetic mechanism in a schizophrenia subgroup that has syndromal overlap with other psychiatric disorders. ME may be triggered by infections, autoimmunity, toxicity, or trauma. A 'late hit' and gene-environment interaction are required to explain major findings about schizophrenia, and both aspects would be consistent with the ME hypothesis. Schizophrenia risk genes stay rather constant within populations despite a resulting low number of progeny; this may result from advantages associated with risk genes, e.g., an improved immune response, which may act protectively within changing environments, although they are associated with the disadvantage of increased susceptibility to psychotic disorders. Specific schizophrenic symptoms may arise with instances of LLNI when certain brain functional systems are involved, in addition to being shaped by pre-existing liability factors. Prodrome phase and the transition to a diseased status may be related to LLNI processes emerging and varying over time. The variability in the course of schizophrenia resembles the varying courses of autoimmune disorders, which result from three required factors: genes, the environment, and the immune system. Preliminary criteria for subgrouping neurodevelopmental, genetic, ME, and other types of schizophrenias are provided. A rare example of ME schizophrenia may be observed in Borna disease virus infection. Neurodevelopmental schizophrenia due to early infections has been estimated by others to explain approximately 30% of cases, but the underlying pathomechanisms of transition to disease remain in question. LLNI (e.g. from reactivation related to persistent infection) may be involved and other pathomechanisms including dysfunction of the blood-brain barrier or the blood-CSF barrier, CNS-endogenous immunity and the volume transmission mode balancing wiring transmission (the latter represented mainly by synaptic transmission, which is often described as being disturbed in schizophrenia). Volume transmission is linked to CSF signaling; and together could represent a common pathogenetic link for the distributed brain dysfunction, dysconnectivity, and brain structural abnormalities observed in schizophrenia. In addition, CSF signaling may extend into peripheral tissues via the CSF outflow pathway along brain nerves and peripheral nerves, and it may explain the peripheral topology of neuronal dysfunctions found, like in olfactory dysfunction, dysautonomia, and even in peripheral tissues, i.e., the muscle lesions that were found in 50% of cases. Modulating factors in schizophrenia, such as stress, hormones, and diet, are also modulating factors in the immune response. Considering recent investigations of CSF, the ME schizophrenia subgroup may constitute approximately 40% of cases. [PubMed Citation] [Order full text from Infotrieve]

13) Harvey L, Boksa P
Prenatal and postnatal animal models of immune activation: Relevance to a range of neurodevelopmental disorders: Developmental Neurobiology Special Issue: Neuroimmunology in Development and Disease.
Dev Neurobiol. 2012 Jun 25;
Epidemiological evidence has established links between immune activation during the prenatal or early postnatal period and increased risk of developing a range of neurodevelopment disorders in later life. Animal models have been used to great effect to explore the ramifications of immune activation during gestation and neonatal life. A range of behavioural, neurochemical, molecular and structural outcome measures associated with schizophrenia, autism, cerebral palsy and epilepsy have been assessed in models of prenatal and postnatal immune activation. However, the epidemiology-driven disease-first approach taken by some studies can be limiting and, despite the wealth of data, there is a lack of consensus in the literature as to the specific dose, timing and nature of the immunogen that results in replicable and reproducible changes related to a single disease phenotype. In this review we highlight a number of similarities and differences in models of prenatal and postnatal immune activation currently being used to investigate the origins of schizophrenia, autism, cerebral palsy, epilepsy and Parkinson's disease. However, we describe a lack of synthesis not only between but also within disease-specific models. Our inability to compare the equivalency dose of immunogen used is identified as a significant yet easily remedied problem. We ask whether early life exposure to infection should be described as a disease-specific or general vulnerability factor for neurodevelopmental disorders and discuss the implications that either classification has on the design, strengths and limitations of future experiments. © 2012 Wiley Periodicals, Inc. Develop Neurobiol, 2012. [PubMed Citation] [Order full text from Infotrieve]

14) Chen SL, Lee SY, Chang YH, Chen SH, Chu CH, Tzeng NS, Lee IH, Chen PS, Yeh TL, Huang SY, Yang YK, Lu RB
Inflammation in Patients with Schizophrenia: The Therapeutic Benefits of Risperidone Plus Add-On Dextromethorphan.
J Neuroimmune Pharmacol. 2012 Jun 23;
Increasing evidence suggests that inflammation contributes to the etiology and progression of schizophrenia. Molecules that initiate inflammation, such as virus- and toxin-induced cytokines, are implicated in neuronal degeneration and schizophrenia-like behavior. Using therapeutic agents with anti-inflammatory or neurotrophic effects may be beneficial for treating schizophrenia. One hundred healthy controls and 95 Han Chinese patients with schizophrenia were tested in this double-blind study. Their PANSS scores, plasma interleukin (IL)-1?, tumor necrosis factor-? (TNF-?) and brain-derived neurotrophic factor (BDNF) levels were measured before and after pharmacological treatment. Pretreatment, plasma levels of IL-1? and TNF-? were significantly higher in patients with schizophrenia than in controls, but plasma BDNF levels were significantly lower. Patients were treated with the atypical antipsychotic risperidone (Risp) only or with Risp+ dextromethorphan (DM). PANSS scores and plasma IL-1? levels significantly decreased, but plasma TNF-? and BDNF levels significantly increased after 11 weeks of Risp treatment. Patients in the Risp+ DM group showed a greater and earlier reduction of symptoms than did those in the Risp-only group. Moreover, Risp+ DM treatment attenuated Risp-induced plasma increases in TNF-?. Patients with schizophrenia had a high level of peripheral inflammation and a low level of peripheral BDNF. Long-term Risp treatment attenuated inflammation and potentiated the neurotrophic function but also produced a certain degree of toxicity. Risp+ DM was more beneficial and less toxic than Risp-only treatment.Clinical Trial Registration: Protocol Record: HR-93-50; Trial Registration number: NCT01189006; URL: [PubMed Citation] [Order full text from Infotrieve]

15) Hung CC, Loh el-W, Hu TM, Chiu HJ, Hsieh HC, Chan CH, Lan TH
Prevalence of hepatitis B and hepatitis C in patients with chronic schizophrenia living in institutions.
J Chin Med Assoc. 2012 Jun;75(6):275-80.
[PubMed Citation] [Order full text from Infotrieve]

16) Khandaker GM, Zimbron J, Lewis G, Jones PB
Prenatal maternal infection, neurodevelopment and adult schizophrenia: a systematic review of population-based studies.
Psychol Med. 2012 Apr 16;:1-19.
BACKGROUND: Disruption of foetal development by prenatal maternal infection is consistent with a neurodevelopmental model of schizophrenia. Whether specific prenatal infections are involved, their timing and the mechanisms of any effect are all unknown. We addressed these questions through a systematic review of population-based studies.MethodElectronic and manual searches and rigorous quality assessment yielded 21 studies that included an objective assessment of individual-level prenatal maternal infection and standardized psychotic diagnoses in adult offspring. Methodological differences between studies necessitated a descriptive review. RESULTS: Results for prenatal maternal non-specific bacterial, respiratory or genital and reproductive infection differed between studies, which reported up to a two- to fivefold increased risk of schizophrenia. Evidence for herpes simplex virus type 2 (HSV-2) and Toxoplasma gondii was mixed; some studies reported up to a doubling of schizophrenia risk. Prenatal HSV-1 or cytomegalovirus (CMV) infections were not associated with increased risk. Exposure to influenza or other infections during early pregnancy may be more harmful than later exposure. Increased proinflammatory cytokines during pregnancy were also associated with risk. Prenatal infection was associated with structural and functional brain abnormalities relevant to schizophrenia. CONCLUSIONS: Prenatal exposure to a range of infections and inflammatory responses may be associated with risk of adult schizophrenia. Larger samples, mediation and animal models should be used to investigate whether there is a 'sensitive period' during development, and the 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. [PubMed Citation] [Order full text from Infotrieve]

17) Khandaker GM, Zimbron J, Dalman C, Lewis G, Jones PB
Childhood infection and adult schizophrenia: A meta-analysis of population-based studies.
Schizophr Res. 2012 Aug;139(1-3):161-8.
[PubMed Citation] [Order full text from Infotrieve]

18) Naviaux RK
Oxidative Shielding or Oxidative Stress?
J Pharmacol Exp Ther. 2012 Jun 13;
In this review I report evidence that the mainstream field of oxidative damage biology has been running fast in the wrong direction for over 50 years. Reactive oxygen species (ROS) and chronic oxidative changes in membrane lipids and proteins found in many chronic diseases are not the result of accidental damage. Instead, these changes are the result of a highly evolved, stereotyped, and protein-catalyzed "oxidative shielding" response that all eukaryotes adopt when placed in a chemically or microbially hostile environment. The machinery of oxidative shielding evolved from pathways of innate immunity designed to protect the cell from attack and to limit the spread of infection. Both oxidative and reductive stress trigger oxidative shielding. In the cases in which it has been studied explicitly, functional and metabolic defects occur in the cell before the increase in reactive oxygen species (ROS) and oxidative changes. ROS are the response to disease, not the cause. Therefore, it is not the oxidative changes that should be targeted for therapy, but rather the metabolic conditions that create them. This fresh perspective is relevant to diseases that range from autism, Type 1 diabetes, Type 2 diabetes, cancer, heart disease, schizophrenia, Parkinson's disease and Alzheimer disease. Research efforts need to be redirected. Oxidative shielding is protective and is a misguided target for therapy. Identification of the causal chemistry and environmental factors that trigger innate immunity and metabolic memory that initiate and sustain oxidative shielding is paramount for human health. [PubMed Citation] [Order full text from Infotrieve]

19) Mirza RA, Eick-Cost A, Otto JL
The risk of mental health disorders among U.S. military personnel infected with human immunodeficiency virus, active component, U.S. Armed Forces, 2000-2011.
MSMR. 2012 May;19(5):10-3.
Mental health disorders (MHD) are reportedly more common among soldiers and airmen with HIV than their seronegative counterparts. This report documents the incidence rates of MHD among HIV-positive members of all service branches and compares the rates to those of two HIV-unexposed control groups: an HSV2-infected group and a group without documented HIV or HSV2 infections. Approximately 56 percent of HIV-infected service members received an incident diagnosis of a MHD six months or more after the initial detection of their infections. Cumulative incidence rates in nearly all MHD categories of interest were highest in the HIV group, intermediate in the HSV2 group and lowest in the referent group. The disorders more frequently diagnosed among HIV-infected service members compared to their uninfected counterparts were psychosis/schizophrenia, substance dependence, substance abuse, bipolar disorder, suicide ideation and depression. The findings are consistent with previous studies and reiterate the importance of long-term and comprehensive clinical monitoring of individuals diagnosed with HIV-1 infections. [PubMed Citation] [Order full text from Infotrieve]

20) Itzhaky D, Amital D, Gorden K, Bogomolni A, Arnson Y, Amital H
Low serum vitamin D concentrations in patients with schizophrenia.
Isr Med Assoc J. 2012 Feb;14(2):88-92.
[PubMed Citation] [Order full text from Infotrieve]