11 March 2008. The old notion that infections contribute to schizophrenia has caught on again, and two prospective studies in the January issue of the American Journal of Psychiatry illustrate the increased scrutiny it has been garnering. Most investigations of the germ theory of schizophrenia have focused on prenatal infections (see SRF related news story), but the brain’s continued development after birth raises the question of whether infections in children and adults raise schizophrenia risk. Accordingly, Christina Dalman and colleagues at the Karolinska Institutet in Stockholm examined infections of the central nervous system (CNS) in a cohort of over a million children. Other researchers, led by David Niebuhr, at the Walter Reed Army Institute of Research in Silver Spring, Maryland, and Johns Hopkins University School of Medicine in nearby Baltimore, used serum samples routinely collected by the United States military to evaluate the effects of exposure to Toxoplasma gondii before schizophrenia onset.
Unfortunately, the ecologic studies that dominate this field of research have lacked data on individuals’ exposure to infectious agents. Furthermore, Dalman and colleagues write, “Data concerning childhood exposures to both bacterial and viral CNS infections and the risk of subsequent psychosis are sparse and contradictory.”
Studies implicate parasite, viruses, but not bacteria
Dalman and associates analyzed data on all of the children in Sweden who were born from 1973 to 1985. Through the Swedish National Inpatient Register, they identified those who had been hospitalized for a bacterial (N = 2,435) or viral (N = 6,550) CNS infection before age 12. They also identified 2,269 subjects who were diagnosed with a nonaffective psychotic illness by the year 2002. Only 23 of them, including eight with schizophrenia, had received hospital care for a CNS infection.
As to what the study found, the investigators write, “There was a slightly increased risk, at the limit of statistical significance (risk ratio = 1.5, 95 percent CI = 1.0-2.4) of developing a nonaffective psychosis (including schizophrenia) later in life if a child had been exposed to a viral CNS infection.” Being female raised that risk (risk ratio = 2.3, 95 percent CI = 1.3-7.3), whereas bacterial infections did not seem to affect risk at all. Narrowing the outcome to schizophrenia did not change the results.
Efforts to pinpoint the specific pathogens involved vindicated enterovirus infections, but implicated mumps (risk ratio = 2.7, 95 percent CI = 1.2-6.1) and cytomegalovirus (risk ratio = 16.6, 95 percent CI = 4.3- 65.1). “It should, however, be noted that the numbers are small, and the results concerning specific infectious agents should therefore be interpreted with caution,” Dalman and colleagues write. Even so, they point out, both viruses invade periventricular parts of the brain and then the brain parenchyma.
While Dalman’s study did not look at Toxoplasma gondii, a recent meta-analysis (Torrey et al., 2007) of over 50 years’ worth of published and unpublished studies from 17 countries found that subjects with schizophrenia were nearly three times likelier than control subjects to harbor antibodies to the protozoan parasite (see SRF Forum Discussion). It triggers flu-like symptoms in people with healthy immune systems, but can form cysts in the brain and lie dormant for years.
“In previous studies, T. gondii antibodies were measured after diagnosis, raising the possibility that the increased levels of antibodies were the result of disease-related environmental factors,” Niebuhr and colleagues write. Yet, proving causality requires showing that the infection preceded schizophrenia. To surmount this problem, the researchers analyzed serum samples collected at military service members’ entry medical exam, later at 3 to 24 months before the schizophrenia diagnosis, and as soon as possible after diagnosis. They compared 180 subjects who had been discharged with a schizophrenia-related disability and 532 healthy subjects.
The study assessed levels of immunoglobulin G (IgG) and immunoglobulin M (IgM) to T. gondii, as well as IgG antibodies to influenza A and B and six herpesviruses. IgM represents the first line of defense against a new antigen; IgG, the body’s most common type of immunoglobulin, responds to repeated invasions by the same germ. In proportional hazards models, IgG, but not IgM, levels to T. gondii correlated with increased schizophrenia risk (hazard ratio = 1.24, 95 percent CI = 1.12-1.37), which persisted after controlling for eight viruses.
The availability of pre-diagnosis exposure data boosts confidence that T. gondii actually contributes to schizophrenia. However, since the microbe infects about one in five Americans, Niebuhr and colleagues question why only a few subjects developed schizophrenia. They suggest that individual reactions to T. gondii exposure “may be related to genetic determinants of host susceptibility, varying degrees of pathogenicity among infecting organisms, or unidentified environmental factors.”
The Niebuhr study hints that, in addition to T. gondii, human herpesvirus 6 may also increase schizophrenia liability (hazard ratio = 1.20, 95 percent CI=1.06-1.35). In fact, a recent study of prenatal infections fingered a different herpesvirus. As described in a November 2 advance online publication in Biological Psychiatry, Stephen Buka of Brown University and associates compared serum samples from 200 adults with psychosis and 554 matched control subjects. Those whose mothers had shown signs of infection with herpes simplex virus-2 just before giving birth were more prone than control subjects to develop psychosis (O.R. = 1.6, 95 percent CI = 1.1-2.3).
Untangling infection from mom’s immune response
Given the variety of microbes that could give rise to psychosis, Buka and associates deem it unlikely that any one of them independently harms the fetal brain. Rather, they write, “We speculate that the pathophysiological process underlying the current results may not be specific to the herpes virus, per se, but rather may result from general enhanced maternal immune activation, which has been shown in animals to result in abnormalities of both dopaminergic activity and cognitive function in the offspring, consistent with deficits observed in patients with schizophrenia.”
While all of these studies move the literature forward, they cannot quell those nagging feelings that something related to infections might be the real actor. For example, a team of researchers, including Paul Patterson and first author Stephen Smith, at the California Institute of Technology in Pasadena, write, “Several lines of evidence indicate that the maternal immune response, rather than direct infection of the fetus, is responsible for the increased incidence of schizophrenia and autism in the offspring of mothers who suffer infections during pregnancy.” In the October 3 Journal of Neuroscience, Smith and colleagues used a mouse model to show that activation of the mother’s immune response in the absence of infection produced behavioral deficits that they liken to those seen in schizophrenia. They presented evidence that interleukin-6, a cytokine involved in the inflammatory response, mediates this effect.
The gene-infection nexus
Robert Yolken and E. Fuller Torrey posit that microbes such as T. gondii and cytomegalovirus may interact with genes to cause schizophrenia (Yolken and Torrey, 2008). If true, germs’ effects on gene expression and the brain may depend on when they strike, according to a team led by S. Hossein Fatemi of the University of Minnesota Medical School in Minneapolis.
Previous work by Fatemi and colleagues had uncovered evidence of impaired brain structure and function in mice born of mothers that had been infected with the flu virus late in the first trimester of pregnancy. The researchers wondered whether infecting the mother later, in the second trimester, would produce a different set of changes. In the February issue of Schizophrenia Research, they report that findings from their comparisons of infected and uninfected male progeny “support the notion that prenatal influenza infection can indeed precipitate altered patterns of gene expression, and neuroanatomic abnormalities in the developing brain.”
Flu-exposed offspring showed changes in the expression of certain genes that have been connected to schizophrenia, including semaphorin 3A, v-erb-B2 avian erythryoblastic leukemia viral oncogene, transferrin receptor 2, and very low-density lipoprotein receptor. Exposed mice also had abnormal levels of serotonin, its metabolite 5-hydroxyindoleacetic acid, and taurine, as well as the Foxp2 protein. Brain imaging indicated that their brains had shrunk and their white matter in the corpus callosum had thinned. As for timing, Fatemi and colleagues write, “It appears that the effect of viral infection early in pregnancy is not nearly as dramatic as at later time points.”
The most stubborn questions about the role of microbes in psychosis relate to timing and causality, according to Yolken and Torrey. The current crop of studies has tried to tackle these issues but, as Alan Brown of New York State Psychiatric Institute in New York City contends, ferreting out definitive answers will require larger, population-based studies with greater statistical power. In an editorial accompanying the Dalman and Niebuhr papers, he writes, “It will be critical in future work to identify susceptibility genes and other developmental precursors that act to modify and mediate the effects of infection on schizophrenia risk.”—Victoria L. Wilcox.
Dalman C, Allebeck P, Gunnell D, Harrison G, Kristensson K, Lewis G, Lofving S, Rasmussen F, Wicks S, Karlsson H. Infections in the CNS during childhood and the risk of subsequent psychotic illness: A cohort study of more than one million Swedish subjects. Am J Psychiatry. 2008 Jan;165(1):59-65. Abstract
Niebuhr DW, Millikan AM, Cowan DN, Yolken R, Li Y, Weber NS. Selected infectious agents and risk of schizophrenia among U.S. military personnel. Amer J Psychiatry. 2008 Jan;165(1):99-106. Abstract
Brown AS. The risk for schizophrenia from childhood and adult infections. Am J Psychiatry. 2008 Jan;165(1):7-10. Abstract
Buka SL, Cannon TD, Torrey EF, Yolken RH, and the Collaborative Study Group on the Perinatal Origins of Severe Psychiatric Disorders. Maternal exposure to herpes simplex virus and risk of psychosis among adult offspring. Biol Psychiatry. 2007 Nov 2 (Epub ahead of print). Abstract
Smith SEP, Li J, Garbett K, Mirnics K, Patterson PH. Maternal immune activation alters fetal brain development through interleukin-6. J Neurosci. 2007 Oct 3;27(40):10695-10702. Abstract
Fatemi SH, Reutiman TJ, Folsom TD, Huang H, Oishi K, Mori S, Smee DF, Pearce DA, Winter C, Sohr R, Juckel G. Maternal infection leads to abnormal gene regulation and brain atrophy in mouse offspring: Implications for genesis of neurodevelopmental disorders. Schizophr Res. 2008 Feb;99(1-3). Epub 2008 Jan 9. Abstract