© Springer International Publishing Switzerland 2015
Norbert Müller, Aye-Mu Myint and Markus J. Schwarz (eds.)Immunology and PsychiatryCurrent Topics in Neurotoxicity810.1007/978-3-319-13602-8_77. Exposure to Microorganisms and Adult Psychiatric Disorders: The Case for a Causal Role of Toxoplasma gondii
(1)
Stanley Division of Developmental Neurovirology, Department of Pediatrics, Johns Hopkins University School of Medicine, 600 N. Wolfe Street, Blalock 1105, Baltimore, MD 21287-4933, USA
(2)
The Stanley Medical Research Institute, 8401 Connecticut Avenue, Suite 200, Chevy Chase, MD 20815, USA
Abstract
Since the 1970s there has been an increasing interest in infectious agents as possible causes of serious mental illness. The microorganism which has been most intensively studied is Toxoplasma gondii, a parasite carried by felines. Several lines of research have suggested that T. gondii is associated with schizophrenia: increased prevalence of T. gondii antibodies in individuals with this disease, and in mothers who give birth to individuals who later are so diagnosed; increased childhood contact with cats by individuals who later are so diagnosed; the fact that T. gondii affects several neurotransmitters and makes dopamine; and the fact that some antipsychotics suppress T. gondii. But is there any evidence that this association is etiological? Austin Bradford Hill published criteria for assessing possible etiological associations between environmental factors and complex diseases. His criteria include strength of association, consistency of findings, specificity of findings, temporality of relationship, biological gradient, plausibility of relationship, coherence of relationship, analogy with other data, and experimental data. Using these criteria, it is concluded that an etiological relationship between T. gondii and some cases of schizophrenia is reasonable.
Keywords
Toxoplasma gondii Hill criteriaCausationInfectious diseaseSchizophreniaIntroduction
The idea that infectious agents may cause serious psychiatric disorders has a long history. As early as the fifteenth century Bartholomew, a Franciscan friar in England, wrote that “insanity may come as the result of an infection, from the bite of a mad dog or some other venomous animal” (Graham 1967). In 1874, as bacteria were being discovered, the American Journal of Insanity published a long article “On the Germ-Theory of Disease” (Drecke 1874). In 1896, the Scientific American published a paper with a title asking “Is Insanity Due to a Microbe?” It described the work of American researchers who believed that bacteria caused insanity and were injecting sera from individuals with insanity into rabbits to ascertain the effect. It reported that the rabbits became sick, “although it is not alleged that they were insane” (Scientific American 1896).
The subsequent discovery of spirochetes as the cause of syphilis, which in its late stages often includes psychotic symptoms, strengthened the infectious theory. This was followed by the case of psychoses associated with the 1918–1919 pandemic of influenza. Karl Menninger summarized 39 such cases and said that he was “persuaded that dementia praecox is at least in most instances a somatopsychosis, the psychic manifestations of an encephalitis” (Menninger 1922, 1926). A Danish psychiatrist agreed that the “toxi-infection” hypothesis of dementia praecox “might…explain the difficulties which have arisen owing to heredo-biological and endocrinological investigations and their divergent results (Reiter 1926).
For the next half century there was comparatively little interest in infectious theories of serious psychiatric disorders. However, beginning in the early 1970s there was a revival of interest in this hypothesis (Torrey and Peterson 1973) and in 1983 the World Health Organization sponsored a symposium on “Research on the Viral Hypothesis of Mental Disorders” (Morozov 1983). Since that time, interest in infectious agents, interacting with predisposing genes, has steadily increased as possible etiological agents for serious mental illness, especially in recent years as inflammatory aspects of these diseases have become prominent.
In a single chapter it is impossible to review the large number of infectious agents that have been investigated during the last three decades. We will therefore focus on Toxoplasma gondii the infectious agent which has been most extensively studied in terms of association with psychiatric disorders. We will then discuss the nature of causal relationships for infectious agents and chronic diseases, including on the use of the Hill criteria of causation, first proposed by Austin Bradford Hill in 1965 and widely used to define associations between environmental exposures and chronic disorders (Hill 1965).
The Biology of T. gondii
T. gondii is a coccidian protozoan of the apicomplexa family, first described in 1908. Felines, including domestic cats, are its definitive host, and the organism can only complete the sexual part of its life cycle within feline hosts. T. gondii oocysts are excreted in the feces of cats at the time they are initially infected. The oocysts may then become aerosolized and infect humans who are changing cat litter boxes, gardening, or playing in sandboxes. The cat may also deposit feces on the ground or in animal feed in barns; domestic animals may eat it, producing T. gondii tissue cysts in their muscles, which then infect humans who eat undercooked meat. Oocysts shed by infected felines can also contaminate water, with subsequent infection of humans through drinking water, eating vegetables, washed with contaminated water, or eating undercooked fish that had lived in the contaminated water. The relative importance of different modes of transmission depends upon local geographic, cultural, and socioeconomic facts. T. gondii is distributed worldwide and infects between 10 and 80 % of the adult population; in the USA, the rate is between 10 and 20 % in young adults.
Infection of pregnant women with T. gondii can produce stillbirths as well as deafness, seizures, cerebral palsy, damage to the retina, or mental retardation in the offspring. In individuals who are immunosuppressed, such as those with AIDS or those undergoing organ transplantation or cancer chemotherapy, infection with or reactivation of T. gondii can produce psychiatric symptoms, including delusions and hallucinations (Kramer 1966). Until recently it was assumed that the infection of immunocompetent, non-pregnant individuals did not pose a health risk but that assumption is now in question. For example, individuals exposed to Toxoplasma through ingestion of contaminated water have shown clear signs of systemic infection at defined times after their exposure (Jones and Dubey 2010).
Association Between Toxoplasma Exposure and Risk of Psychiatric Disorders
Studies indicating that exposure to T. gondii might be associated with increased risk of schizophrenia are summarized as follows:
Antibodies against T. gondii are increased in individuals with serious mental illness, especially schizophrenia.
A meta-analysis of 38 studies of T. gondii antibodies in individuals with schizophrenia, compared to non-affected controls, reported that the prevalence of T. gondii antibodies was higher in 36 of the studies (OR 2.71; 95 % CI 1.93–3.80) (Torrey et al. 2012). Another study collected sera from 45,609 women at the time they gave birth. During the following 16 years, 80 of the women developed schizophrenia; those with the highest T. gondii IgG antibody levels at the time they gave birth had a significantly increased chance of developing schizophrenia (Pedersen et al. 2011). Four studies have reported an increased prevalence of T. gondii antibodies in individuals with bipolar disorder (Fekadu et al. 2010; Pearce et al. 2012; Hamdani et al. 2013; Nascimento et al. 2012) and one study reported that such antibodies are increased in individuals with obsessive-compulsive disorder (Miman et al. 2010)
T. gondii is known to affect some neurotransmitters known to be abnormal in serious mental illnesses.
It is known that T. gondii is highly neurotropic and infects both neurons and glia. One study in cell culture reported that T. gondii affected the expression of RNA sequences associated with dopamine, glutamate, and serotonin and that these effects varied significantly depending on the strain of T. gondii (Xiao et al. 2013). Another study in mice reported that T. gondii affects the GABA neurotransmitter system (Fuks et al. 2012). The effect of T. gondii on dopamine is especially interesting since dopamine has been assumed to be increased in individuals with schizophrenia and many of the antipsychotic drugs used to successfully treat schizophrenia block dopamine. It is now known that T. gondii makes dopamine, raising the possibility that the excess dopamine which occurs in schizophrenia may be a product of the infecting agent and not being made by the individual affected (Prandovszky et al. 2011).Related posts:
Experimental Human Endotoxemia, Sickness Behavior, and Neuropsychiatric Diseases
Developmental Immune Activation Models with Relevance to Schizophrenia
The Role of Inflammation in Alzheimer’s Disease
Microglia Activation, Herpes Infection, and NMDA Receptor Inhibition: Common Pathways to Psychosis?
The Role of Infections and Autoimmune Diseases for Schizophrenia and Depression: Findings from Large-Scale Epidemiological Studies
Animal Models Based on Immune Challenge: The Link to Brain Changes and Schizophrenia
Stay updated, free articles. Join our Telegram channel
Full access? Get Clinical Tree
