Catching Schizophrenia? Studies Revisit Germ Theory
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
Comments on News and Primary Papers
Primary Papers: The risk for schizophrenia from childhood and adult infections.Comment by: Mohammed Ali Warsi
Submitted 14 January 2008
Posted 14 January 2008
I recommend this paper
Comments on Related News
Related News: Bad Timing: Prenatal Exposure to Maternal STDs Raises Risk of SchizophreniaComment by: Paul Patterson
Submitted 22 May 2006
Posted 22 May 2006
Over the past six years, Alan Brown and colleagues have published an impressive series of epidemiological findings on schizophrenia in the offspring of a large cohort of carefully studied pregnant women (reviewed by Brown, 2006). Their work has confirmed and greatly extended prior findings linking maternal infection in the second trimester with increased risk for schizophrenia in the offspring. Moreover, Brown et al. found an association between anti-influenza antibodies in maternal serum and increased risk for schizophrenia, as well as a similar association with elevated levels of a cytokine in maternal serum. In a new paper (Babulas et al., 2006), this group reports a fivefold increase in risk for schizophrenia spectrum disorders in the offspring of women who experienced a genital/reproductive infection during the periconception period. The infections considered were endometritis, cervicitis, pelvic inflammatory disease, vaginitis, syphilis, condylomata, “venereal disease,” and gonorrhea. Strengths of the study include physician documentation of the infections and face-to-face assessments of schizophrenia. Although sample size was modest, these results extend a prior finding that elevated maternal anti-herpes simplex type 2 antibodies are associated with increased risk of psychotic disorders, including schizophrenia (Buka et al., 2001).
The mechanism of how maternal infection increases risk for schizophrenia could involve pathogens invading the fetus. Although this is certainly possible in the case of some of the infections studied by Babulas et al., in the case of a respiratory virus such as influenza, this explanation appears unlikely. A more parsimonious mechanism would involve activation of the maternal immune system, and action of soluble mediators such as cytokines at the level of the placenta or the fetus. Support for this hypothesis comes from animal studies. An antiviral immune response can be evoked in the absence of the pathogen by injection of synthetic double-stranded RNA (polyI:C). When this is done in pregnant rats or mice, the adult offspring display a number of behavioral abnormalities reminiscent of those observed in schizophrenia. These include deficits in prepulse inhibition, latent inhibition, and social interaction, as well as enhanced amphetamine-induced locomotion and anxiety under mildly stressful conditions (Shi et al., 2003; Zuckerman et al., 2003; Ozawa et al., 2005). Moreover, some of these deficits are ameliorated by treatment with antipsychotic drugs and exacerbated by psychotomimetics (Shi et al., 2003; Ozawa et al., 2005), and the offspring also exhibit dopaminergic hyperfunction (Zuckerman et al., 2003; Ozawa et al., 2005). Some of these abnormalities are also seen in the offspring of influenza-infected mothers or mothers injected with the bacterial cell wall component, LPS (Borrell et al., 2002; Fatemi et al., 2002; Shi et al., 2003).
The most recent advance in this growing cottage industry is the finding that there are critical periods of maternal immune activation that determine the type of adult behavioral dysfunction and neuropathology found in the offspring (Meyer et al., 2006). Injection of polyI:C during stages of mouse gestation corresponding to first-to-second versus second-to-third trimesters of human pregnancy yields different deficits in exploratory and perseverative behavior, postnatal reelin expression, and hippocampal apoptosis. Moreover, these two different stages of injection evoke diverse cytokine responses in the fetal brain. It would further be interesting to know which of these abnormalities is specific to the period corresponding to the human second trimester, as this is the key time of vulnerability for risk of schizophrenia associated with maternal infection.
Other fascinating questions for this increasingly popular model are, what mediates the effects of maternal immune activation (e.g., cytokines, antibodies, corticosteroids), and do they act directly on the fetus or via the placenta? Can imaging be used with the rodents to explore dopamine receptor occupancy? Which of the observed pathologies are most relevant for each of the behavioral abnormalities?
Babulas V, Factor-Litvak P, Goetz R, Schaefer CA, Brown AS. Prenatal exposure to maternal genital and reproductive infections and adult schizophrenia. Am J Psychiatry. 2006 May;163(5):927-9. Abstract
Borrell J, Vela JM, Arevalo-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. Abstract
Brown AS. Prenatal infection as a risk factor for schizophrenia.
Schizophr Bull. 2006 Apr;32(2):200-2. Epub 2006 Feb 9.
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. 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. Abstract
Meyer U, Feldon J, Schedlowski M, Yee BK. Towards an immuno-precipitated neurodevelopmental animal model of schizophrenia. Neurosci Biobehav Rev. 2005;29(6):913-47. Abstract
Meyer U, Nyffeler M, Engler A, Urwyler A, Schedlowski M, Knuesel I, Yee BK, Feldon J. The time of prenatal immune challenge determines the specificity of inflammation-mediated brain and behavioral pathology. J Neurosci. 2006 May 3;26(18):4752-62. Abstract
Ozawa K, Hashimoto K, Kishimoto T, Shimizu E, Ishikura H, Iyo M. Immune activation during pregnancy in mice leads to dopaminergic hyperfunction and cognitive impairment in the offspring: a neurodevelopmental animal model of schizophrenia. Biol Psychiatry. 2006 Mar 15;59(6):546-54. Epub 2005 Oct 26. 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.
Zuckerman L, Rehavi M, Nachman R, Weiner I. Immune activation during pregnancy in rats leads to a postpubertal emergence of disrupted latent inhibition, dopaminergic hyperfunction, and altered limbic morphology in the offspring: a novel neurodevelopmental model of schizophrenia. Neuropsychopharmacology. 2003 Oct;28(10):1778-89. Abstract
View all comments by Paul Patterson
Related News: Bad Timing: Prenatal Exposure to Maternal STDs Raises Risk of Schizophrenia
Comment by: Jürgen Zielasek
Submitted 3 June 2006
Posted 3 June 2006
Meyer and coworkers provide interesting new data on the role of the immune system in mediating the damage caused by viral infections during pregnancy on the developing nervous system of the fetus. Not just the timing of the infection appears to be critical, but the developing fetal immune system appears to play a role, too.
Polyinosinic-polycytidylic acid (polyI:C), which was employed by Meyer et al., is frequently used to mimic viral infections. It is a synthetic double-stranded RNA and has adjuvant-effects (Salem et al., 2005). PolyI:C binds to target cells via the "Toll-like receptor 3" (TLR3). TLR3 serves as a receptor in trophoblast cells and uterine epithelial cells mediating local immune activation at the maternal-fetal interface after viral infections (Abrahams et al., 2005; Schaefer et al., 2005). Glial cells like microglia and astrocytes also express functional TLR3 (Farina et al., 2005; Park et al., 2006; Town et al., 2006). Thus, TLR3 plays an important role in immune responses, and its natural function appears to be immune activation in addition to cross-priming the immune system to virus-infected cells (Schulz et al., 2005). Given the expression of TLR3 at the maternal-fetal interface and on glial cells, the polyI:C-TLR3-model appears to be useful to study the basic mechanisms of viral infections and their consequences for brain development in animal models.
However, several limitations are evident: PolyI:C is not a virus, and different immunological pathways may be activated by intact viruses after binding to their appropriate receptors. Findings from the immune system of rodents cannot be directly transferred to humans, and it may be difficult to dissect—on a molecular level—the protective aspects of an immune response against a viral infection from its putative detrimental effects on human neurodevelopment. Still, such mechanisms may now be studied in the rodent models used by Meyer and coworkers and other groups, and this will help to pave the way for future studies in humans. This will hopefully lead to a better understanding of the role of the immune system and viral infections in the pathogenesis of schizophrenia.
Abrahams VM, Visintin I, Aldo PB, Guller S, Romero R, Mor G. A role for TLRs in the regulation of immune cell migration by first trimester trophoblast cells.
J Immunol. 2005 Dec 15;175(12):8096-104.
Farina C, Krumbholz M, Giese T, Hartmann G, Aloisi F, Meinl E. Preferential expression and function of Toll-like receptor 3 in human astrocytes.
J Neuroimmunol. 2005 Feb;159(1-2):12-9. Epub 2004 Nov 11.
Park C, Lee S, Cho IH, Lee HK, Kim D, Choi SY, Oh SB, Park K, Kim JS, Lee SJ. TLR3-mediated signal induces proinflammatory cytokine and chemokine gene expression in astrocytes: differential signaling mechanisms of TLR3-induced IP-10 and IL-8 gene expression.
Glia. 2006 Feb;53(3):248-56.
Salem ML, Kadima AN, Cole DJ, Gillanders WE. Defining the antigen-specific T-cell response to vaccination and poly(I:C)/TLR3 signaling: evidence of enhanced primary and memory CD8 T-cell responses and antitumor immunity.
J Immunother. 2005 May-Jun;28(3):220-8.
Schaefer TM, Fahey JV, Wright JA, Wira CR. Innate immunity in the human female reproductive tract: antiviral response of uterine epithelial cells to the TLR3 agonist poly(I:C).
J Immunol. 2005 Jan 15;174(2):992-1002.
Schulz O, Diebold SS, Chen M, Naslund TI, Nolte MA, Alexopoulou L, Azuma YT, Flavell RA, Liljestrom P, Reis e Sousa C. Toll-like receptor 3 promotes cross-priming to virus-infected cells.
Nature. 2005 Feb 24;433(7028):887-92. Epub 2005 Feb 13.
Town T, Jeng D, Alexopoulou L, Tan J, Flavell RA. Microglia recognize double-stranded RNA via TLR3. J Immunol. 2006 Mar 15;176(6):3804-12. Abstract
View all comments by Jürgen Zielasek
Related News: Does Toxoplasma Gondii Hijack the Dopamine Reward System of Rats?
Comment by: Fuller Torrey, Robert Yolken
Submitted 2 December 2008
Posted 2 December 2008
The research being carried out by Dr. Sapolsky and colleagues at Stanford is potentially very important for understanding schizophrenia. (In regard to full disclosure, it should be noted that the Stanley Medical Research Institute (SMRI) is funding Dr. Sapolsky’s research as well as other research on dopamine and Toxoplasma gondii.)
The origin of interest in dopamine and T. gondii appears to have been the 1985 paper by Henry H. Stibbs, then in the School of Public Health and Community Medicine at the University of Washington. Stibbs had been studying trypanosomes and sleeping sickness for 10 years and discovered that this organism increased dopamine levels by 34 percent in infected rats (Stibbs, 1984). He therefore turned his attention to T. gondii because of its known ability to alter learning, memory, and behavior in infected mice and rats. He infected 30 mice with the C56 strain of T. gondii. Ten mice were infected, became symptomatic, and were killed at 12 days (= acute group). Ten mice were infected, treated with sulfadiazine, did not develop symptoms, and were killed at five weeks (= chronic group). Ten control mice were also killed at five weeks. The brains were assessed neurochemically and compared to the controls. There were no changes in serotonin or 5-HIAA. Norepinephrine was 28 percent decreased in acute but not in chronic infection. Homovanillic acid (HVA) was 40 percent increased in acute but not chronic infection. Dopamine was normal in acute infection but 14 percent increased in the treated mice with chronic infection. Stibbs concluded that T. gondii causes abnormalities in catecholamine metabolism and that these “may be factors contributing to the psychological and motor changes” seen in experimentally infected rodents (Stibbs, 1985).
Joanne Webster and her colleagues at Oxford infected rats with T. gondii, then treated them with haloperidol, an antipsychotic known to block dopamine. The effect of the haloperidol was to reverse the behavioral effects of T. gondii. They speculated that possible explanatory mechanisms include the ability of haloperidol “to inhibit T. gondii replication and to reduce, directly and indirectly, dopamine levels” (Webster et al., 2006).
Jaroslav Flegr and his colleagues in Prague have studied the effects of T. gondii infection on the behavior of mice. They reported that giving the mice a dopamine reuptake inhibitor (GBR 12909) altered the behavior of the mice and concluded that “the proximal causes of alterations in mice behavior induced by Toxoplasma gondii are probably changes in the dopaminergic system” (Skallová et al., 2006). In other publications, Flegr and colleagues have speculated that dopamine is the “missing link between schizophrenia and toxoplasmosis,” specifically suggesting that dopamine is increased by activated cytokines (e.g., IL–2) as a consequence of infection (Flegr et al., 2003; Flegr, 2007).
The intriguing thing about this research is its possible relevance to schizophrenia. For more than 40 years, it has been clear that an excess of dopamine is somehow involved in the pathogenesis of schizophrenia. Despite hundreds of studies, however, relatively few abnormalities have been identified in the dopamine production of individuals with schizophrenia. If T. gondii is part of the disease’s etiology, the excess dopamine may be being introduced exogenously by the parasite. If true, this would introduce a whole new approach to treatment.
An important aspect of this body of work is that it provides an evolutionary basis for why an infectious agent might lead to altered behavior. In terms of Toxoplasma, this association is based on the organism’s life cycle. The primary host for Toxoplasma is the cat. Toxoplasma organisms can complete their replication cycle, including their sexual stage, within members of the feline species. If other animals become infected, the organisms can undergo some replication but cannot complete the sexual stage. The Toxoplasma organism must thus do something in order to get back into the cat if it is to complete its life cycle. Since the organism cannot get around on its own, it has to alter the behavior of its host if it is to accomplish this vital evolutionary goal. Dr. Sapolsky and others have documented the behavioral alterations associated with Toxoplasma infection. If the host is a rodent, the end result of these alterations is that the rodent gets eaten and the Toxoplasma is quite happy (even if the rodent is obviously not). This may also have been the case for prehistoric humans, who were also the frequent prey of large cats. While getting eaten by cats is not a problem for most modern humans, the Toxoplasma organism does not know this and still attempts to alter the behavior of its host. The vestigial effect of Toxoplasma infection may thus result in the altered behaviors that are the hallmark of schizophrenia, bipolar disorder, and other psychiatric disorders.
A summary of current research on T. gondii and schizophrenia can be found on the SMRI website (Laboratory of Developmental Neurovirology, Toxoplasmosis–Schizophrenia Research).
Stibbs HH, Neurochemical and activity changes in rats infected with Trypanosoma brucei gambiense, J Parasitology 1984;70:428–432. Abstract
Stibbs HH, Changes in brain concentrations of catecholamines and indoleamines in Toxoplasma gondii infected mice, Ann Trop Med Parasitol 1985;79:153–157. Abstract
Webster JP, Lamberton PH, Donnelly CA, Torrey EF. Parasites as causative agents of human affective disorders? The impact of anti-psychotic, mood-stabilizer and anti-parasite medication on Toxoplasma gondii's ability to alter host behaviour. Proc Biol Sci. 2006 Apr 22;273(1589):1023-30. Abstract
Skallová A, Kodym P, Frynta D, Flegr J. The role of dopamine in Toxoplasma-induced behavioural alterations in mice: an ethological and ethopharmacological study. Parasitology. 2006 Nov 1;133(Pt 5):525-35. Abstract
Flegr J, Preiss M, Klose J, Havlícek J, Vitáková M, Kodym P. Decreased level of psychobiological factor novelty seeking and lower intelligence in men latently infected with the protozoan parasite Toxoplasma gondii Dopamine, a missing link between schizophrenia and toxoplasmosis? Biol Psychol. 2003 Jul 1;63(3):253-68. Abstract
Flegr J, Effects of Toxoplasma on human behavior, Schizophr Bull 2007;33:757-760. Abstract
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Related News: Does Toxoplasma Gondii Hijack the Dopamine Reward System of Rats?
Comment by: Tamas Treuer
Submitted 9 December 2008
Posted 9 December 2008
Congratulations to Profs. Sapolsky, Torrey, and Yolken for their important contribution to this field. The question for me is rather an evolutionary one: is there any trace in the neuron-immuno-endocrine system of patients with schizophrenia that can reflect the adaptation to this hijacking attempt of this protozoon? Recent meta-analyses have provided a comprehensive overview of studies investigating Toxoplasma gondii antibodies in schizophrenic patients, thus attempting to clarify the potential role these infections might play in causing schizophrenia (Torrey and Yolken, 2007). Associations and theories that may enrich the current level of knowledge with regard to this significant subject deserve attention. Anti-parasitic agents as well as antipsychotics are effective in treating parasitosis. Both classes of drugs have been shown to exert dopaminergic activity. Parasites and human organisms have a long history of mutual contact. The effect of parasitosis on the host and the host's response to infection are undoubtedly the product of a long evolutionary process. The neurochemical background of delusions of parasitosis is potentially similar to ancient evolutionary traces of altered neurotransmission and neuropeptide gene expression caused by parasites; these include fungal and viral infections. This is very unique in medicine if a class of drugs is effective in the treatment of an illness but also cures the delusion of the same disorder as well. Furthermore, metabolic disturbances such as hyperglycemia and insulin resistance were reported several decades before the antipsychotic era. Toxoplasmosis may also be linked to insulin resistance.
Although it would be important to established treatment trials, specifically by demonstrating that medications suppressing T. gondii infections improve the clinical symptoms of schizophrenia, it is not clear whether this would be a direct link. This experiment would be similar to the observations made in children affected by the PANDAS (Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal infections) syndrome. The term is used to describe children who are believed to have developed obsessive-compulsive disorder (OCD) and/or tic disorders such as the Tourette syndrome following a group-Aβ-hemolytic streptococcal infection. However, studies with PANDAS children have shown that antibiotic treatment is not consistently effective in reducing the infection rate or the severity of obsessive-compulsive and/or tic symptoms in these children. Once the damage has occurred, corrective treatment against the infective agent is not always beneficial.
Schizophrenia research can benefit from understanding this evolutionary link. New chemical entities that are liable to alter neurochemical changes related to the brain's perception of the risk of predation secondary to parasites may result in new approaches for the treatment of psychosis. Neuroendocrine changes in the brain and body of people with schizophrenia are probably ancient traces of survival strategy on these individuals. These findings suggest that further research is needed to clarify this evolutionary link between parasite infection and delusions of parasitosis. I believe this model may well open up new avenues of research in the discovery of drugs to counteract schizophrenia and related disorders (Treuer and Karagianis, 2006; Treuer et al., 2007; Treuer et al., 2008).
Torrey Ef, Yolken RH. Schizophrenia and Toxoplasmosis.
Schizophrenia Bulletin. 2007;33:727-728. Abstract
Treuer T, Martenyi F, Karagianis J: Parasitosis, Dopaminergic Modulation
and Metabolic Disturbances in Schizophrenia: Evolution of a Hypothesis.
NeuroEndocrinology Letters. 2007 Oct;28(5):535-40. Abstract
Treuer T, Karagianis J: Is Hunger a Driver of Cognitive Development?
Neuropsychopharmacology. Oct 2006;(31)10:2326-2327. Abstract
Treuer T, Karagianis J, Hoffmann VP: Can Increased Food Intake Improve
Psychosis? A Brief Review and Hypothesis. Current Molecular Pharmacology.
Treuer T: The Potential Role of Ghrelin in the Mechanism of Sleep
Deprivation Therapy for Depression. Sleep Medicine Reviews. 2007
View all comments by Tamas Treuer
Related News: Does Toxoplasma Gondii Hijack the Dopamine Reward System of Rats?
Comment by: Jaroslav Flegr
Submitted 9 December 2008
Posted 9 December 2008
The results of the research performed by Dr. Sapolsky and colleagues at Stanford, elaborating the results obtained by Drs. Berdoy and Webster at Oxford (Berdoy et al., 2000), are really fascinating. It should not be forgotten, however, that dopamine is not the only suspected molecule. There are several indirect and recently even direct indications for changed levels of testosterone in subjects with latent toxoplasmosis (Flegr et al., 2008). Moreover, the increased levels of dopamine in Toxoplasma infected mice and men seem to be byproducts of local brain inflammations, rather than a product of biologically important manipulation of the host behavior by the parasite. The results from human cytomegalovirus, i.e., the parasite transmitted by direct contact, not by predation, suggest that an infection of brain tissue by various parasites could increase the level of brain dopamine (Skallová et al., 2005). From the point of view of schizophrenia research or even clinical practice, the question of whether the increased level of dopamine is a product of manipulation or a byproduct of brain infection, is, of course, not so important.
Recently, results of several large independent studies suggest that RHD positive subjects, especially heterozygotes, are protected against latent toxoplasmosis-induced impairment of reaction times (Novotná et al., 2008; Flegr et al., 2008). The RhD protein, which is the RHD gene product and a major component of the Rh blood group system, carries the strongest blood group immunogen, the D-antigen. The structure homology data suggest that the RhD protein acts as an ion pump of uncertain specificity and unknown physiological role. The protein is present mainly on the surface of erythrocytes; however, expression library data suggest that the RHD gene is expressed also in brain tissue. It seems to me that possible association between RhD phenotype and schizophrenia should be studied in the future.
Berdoy M, Webster JP, Macdonald DW. Fatal attraction in rats infected with Toxoplasma gondii. Proc Biol Sci. 2000 Aug 7;267(1452):1591-4. Abstract
Flegr J, Lindová J, Kodym P. Sex-dependent toxoplasmosis-associated differences in testosterone concentration in humans. Parasitology. 2008 Apr 1;135(4):427-31. Abstract
Skallová A, Novotná M, Kolbeková P, Gasová Z, Veselý V, Sechovská M, Flegr J. Decreased level of novelty seeking in blood donors infected with Toxoplasma. Neuro Endocrinol Lett. 2005 Oct 1;26(5):480-6. Abstract
Novotná M, Havlícek J, Smith AP, Kolbeková P, Skallová A, Klose J, Gasová Z, Písacka M, Sechovská M, Flegr J. Toxoplasma and reaction time: role of toxoplasmosis in the origin, preservation and geographical distribution of Rh blood group polymorphism. Parasitology. 2008 Sep 1;135(11):1253-61. Abstract
Flegr J, Novotná M, Lindová J, Havlícek J. Neurophysiological effect of the Rh factor. Protective role of the RhD molecule against Toxoplasma-induced impairment of reaction times in women. Neuro Endocrinol Lett. 2008 Aug 1;29(4):475-81. Abstract
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Related News: Does Toxoplasma Gondii Hijack the Dopamine Reward System of Rats?
Comment by: Huan Ngo
Submitted 16 December 2008
Posted 16 December 2008
Drs. Sapolsky's and Vyas's recent body of data have provided significant mechanistic insights into the parasite manipulation hypothesis, the dopamine hypothesis of schizophrenia and the gene-environment etiological paradigm.
Since most of the human epidemiological data currently emphasizes Toxoplasma exposure from the prenatal period, do we know whether maternal infection results in dopamine alteration in the prenatal, neonatal or postnatal amydala? Is the effect caused directly by transplacental migration of the parasite to the prenatal amydala, or indirectly by maternal cytokine effects, such as IL6 or IL8, on the embryonic brain?
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Related News: Does Toxoplasma Gondii Hijack the Dopamine Reward System of Rats?
Comment by: Artyom Tikhomirov
Submitted 18 December 2008
Posted 22 December 2008
It seems like both bacteria and protozoa have been shown to either increase or decrease certain defensin levels in humans (Sperandio et al., 2008; Wiesenfeld et al., 2002). Then there's a single report from Sabine Bahn's group of increased α-defensins in schizophrenia (Craddock et al., 2008). It is interesting to speculate whether Toxoplasma gondii might contribute to the change in defensin levels.
Sperandio B, Regnault B, Guo J, Zhang Z, Stanley SL, Sansonetti PJ, Pédron T. Virulent Shigella flexneri subverts the host innate immune response through manipulation of antimicrobial peptide gene expression. J Exp Med. 2008 May 12;205(5):1121-32. Abstract
Craddock RM, Huang JT, Jackson E, Harris N, Torrey EF, Herberth M, Bahn S. Increased alpha-defensins as a blood marker for schizophrenia susceptibility. Mol Cell Proteomics. 2008 Jul 1;7(7):1204-13. Abstract
Wiesenfeld HC, Heine RP, Krohn MA, Hillier SL, Amortegui AA, Nicolazzo M, Sweet RL. Association between elevated neutrophil defensin levels and endometritis. J Infect Dis. 2002 Sep 15;186(6):792-7. Abstract
View all comments by Artyom Tikhomirov