III. Epidemiological Similarities and Differences Between Toxoplasmosis and Schizophrenia
Epidemiologically, there are at least seven areas of similarity between toxoplasmosis and schizophrenia. There are also at least three areas in which epidemiological aspects are dissimilar.
The areas of similarity are as follows:
· Familial and genetic aspects
The fact that schizophrenia is familial, as demonstrated by family, twin, and adoption studies, is one of the most salient features of this disease. The explanation for this familial pattern is widely assumed to be genetic, and multiple candidate predisposing genes have been identified. Toxoplasmosis has also been observed to be familial, affecting multiple members of the same family, both from having common food exposure and from common exposure to an infected cat (Stagno S, Dykes AC, Amos CS et al., An outbreak of toxoplasmosis linked to cats, Pediatrics 1980;65:706–712; Sacks JJ, Roberto RR, Brooks NF, Toxoplasmosis infection associated with raw goat’s milk, JAMA 1982;248:1728–1732). Animal models of toxoplasmosis have demonstrated that genes influence the susceptibility of animals to T. gondii infection (Johnson J, Suzuki Y, Mack D et al., Genetic analysis of influences on survival following Toxoplasma gondii infection, Int J Parasitol 2002;32:179–185). It is also known that mice with chronic T. gondii infections can pass the infection to their offspring for as many as five successive generations in a pseudogenetic pattern (Beverley JKA, Congenital transmission of toxoplasmosis through successive generations of mice [letter], Nature 1959;183:1348–1349).
· Age of onset
Studies have shown that the peak onset of schizophrenia occurs between the ages of 20 and 30, with results varying depending on whether “onset” is defined by the first symptoms, treatment or hospitalization. Studies have shown a similar peak onset for individuals with recently acquired, adult-onset toxoplasmosis, clinically suggested by lymphadenopathy (see Fig. 1) (Häfner H, Riecher-Rössler A, an der Heiden W et al., Generating and testing a causal explanation of the gender difference in age at first onset of schizophrenia, Psychol Med 1993;23:925–940; Jackson MH, Hutchinson WM, The prevalence of Toxoplasma infection in the environment, Adv Parasitol 1989;28:55–105).
Figure 1. Comparison of age of onset of schizophrenia and toxoplasmosis
Age of onset of schizophrenia as determined by first
admission
Age of onset of adult toxoplasmosis as determined by lymphadenopathy
· Males get sick at a younger age than females
It is clearly established that males develop schizophrenia at an average younger age than females. In studies done in England, the mean age at first admission for schizophrenia was 28.0 for males and 31.8 for females (Watt DC, Szulecka TK, The effect of sex, marriage and age at first admission on the hospitalization of schizophrenics during 2 years following discharge, Psychol Med 1979;9:529–539). The pattern is similar for adult-onset toxoplasmosis; in one study, the mean age of onset was 27.7 for males and 31.9 for females (Ryan M, Hall SM, Barrett NJ et al., Toxoplasmosis in England and Wales 1981 to 1992, Commun Dis Rep CDR Rev 1995;5:R13–21). In another study, three times more males than females became infected under age 15 (Beverley JKA, Fleck DG, Kwantes W, Age-sex distribution of various diseases with particular reference to toxoplasmic lymphadenopathy, J Hyg (Camb) 1976;76:215–228).
· Socioeconomic status and household crowding
In the United States, studies have demonstrated that the prevalence of schizophrenia is higher in individuals who are poorer and who live in more crowded households (Regier DA, Farmer ME, Rae DS et al., One-month prevalence of mental disorders in the United States and sociodemographic characteristics: the Epidemiologic Catchment Area study, Acta Psychiatr Scand 1993;88:35–47; Schweitzer L, Su E-H, Population density and the rate of mental illness, Am J Public Health 1977;67:1165–1172). Similarly, the prevalence of antibodies to T. gondii has been shown to be higher in individuals who are poorer and who live in more crowded households (Kruszon-Moran D, McQuillan GM, Seroprevalence of six infectious diseases among adults in the United States by race/ethnicity: data from the third National Health and Nutrition Examination Survey, Adv Data 2005;352:1–9).
· Association with stillbirths
An increase in stillbirths among mothers with schizophrenia has been reported in five studies (Sobel DE, Infant mortality and malformations in children of schizophrenic women, Psychiatr Q 1961;35:60–65; Rieder RO, Rosenthal D, Wender P et al., The offspring of schizophrenics: fetal and neonatal deaths, Arch Gen Psychiatry 1975;32:200–211; Modrzewska K, The offspring of schizophrenic parents in a North Swedish isolate, Clin Genet 1980;17:191–201; Nilsson E, Lichtenstein P, Cnattingius S et al., Women with schizophrenia: pregnancy outcome and infant death among their offspring, Schizophr Res 2002;58:221–229; Bennedsen BE, Mortensen PB, Olesen AV et al., Congenital malformations, stillbirths, and infant deaths among children of women with schizophrenia, Arch Gen Psychiatry 2001;58:674–679). However, it was not found in a sixth study (Jablensky AV, Morgan V, Zubrick SR et al., Pregnancy, delivery, and neonatal complications in a population cohort of women with schizophrenia and major affective disorders, Am J Psychiatry 2005;162:79–91). An increase in stillbirths has also been documented among women infected with T. gondii during pregnancy (Sever JL, Ellenberg JH, Ley AC et al., Toxoplasmosis: maternal and pediatric findings in 23,000 pregnancies, Pediatrics 1988;82:181–192).
· Geographic low-prevalence toxoplasmosis regions
As has been demonstrated on isolated islands, toxoplasmosis does not exist in places where there are no felines. In areas where felines are rare, the prevalence rates of both toxoplasmosis and schizophrenia appear to be low. The best example is probably the highlands of Papua New Guinea, where until recently, domesticated cats were virtually nonexistent and wild felines comparatively rare. In this area, the percentage of people with antibodies to T. gondii was reported to be 2 percent or less (Wallace GD, Zigas V, Gajdusek DC, Toxoplasmosis and cats in New Guinea, Am J Trop Med Hyg 1974;23:8–14). A 1973 study of the prevalence of schizophrenia in this area also reported it to be among the lowest in the world (Torrey EF, Torrey BB, Burton-Bradley BG, The epidemiology of schizophrenia in Papua New Guinea, Am J Psychiatry 1974;131:567–572).
· Historical trends
Although cats were kept as pets in ancient Egypt, their modern domestication began only in the mid-eighteenth century and then increased rapidly (Champfleury M, The Cat: Past and Present, London: George Bell and Sons, 1885). Some people believe that schizophrenia was a rare disease prior to the mid-eighteenth century but then increased rapidly in incidence. Thus, the increase in keeping cats as pets and the increase in schizophrenia would have coincided (Torrey EF, Miller J, The Invisible Plague: The Rise of Mental Illness from 1750 to the Present, New Brunswick, N.J.: Rutgers University Press, 2001).
The areas in which epidemiological aspects of toxoplasmosis and schizophrenia are dissimilar are as follows:
· Urban-rural differences
Almost all studies have reported that being born in, or having lived as a child in, an urban area, compared to a rural area, confers an increased risk of later being diagnosed with schizophrenia (Mortensen PB, Pedersen CB, Westergaard T et al., Effects of family history and place and season of birth on the risk of schizophrenia, N Engl J Med 1999;340:603–608). By contrast, some studies of antibodies to T. gondii have reported them to be more common in individuals in urban areas, but other studies have reported them to be more common in individuals in rural areas. One summary concluded that such studies have shown “no consistent pattern, with rural predominance in some and urban in others” (Hall S, Ryan M, Buxton D, The epidemiology of Toxoplasma infection, in Joynson DHM, Wreghitt TG (eds), Toxoplasmosis: A Comprehensive Clinical Guide, Cambridge: Cambridge University Press, 2001, pp. 58–124).
· Geographic high-prevalence toxoplasmosis regions
Although geographic areas with a low prevalence of T. gondii antibodies also have a low prevalence of schizophrenia, the opposite is not the case. Individuals in countries such as France, Ethiopia, and Brazil have a high prevalence of antibodies to T. gondii. In France and Ethiopia, the high infection rates are thought to be attributable to the cultural custom of eating undercooked or uncooked meat; in Brazil, the high rate has been attributed to water supplies contaminated with feline oocysts as well as to undercooked meat consumption (Guebre-Xabier M, Nurilign A, Gebre-Hiwot A et al., Sero-epidemiological survey of Toxoplasma gondii infection in Ethiopia, Ethiop Med 1993;31:201–208; Bahia-Oliveira LMG, Jones JL, Azevedo-Silva J et al., Highly endemic, waterborne toxoplasmosis in North Rio de Janeiro State, Brazil, Emerg Infect Dis 2003;9:55–62). By contrast, studies of the prevalence of schizophrenia in these countries have not suggested that they have unusually high rates by world standards.
· Historical trends
There are multiple reports that the seroprevalence of toxoplasmosis has decreased sharply in the United States and Europe in the past forty years. It has been speculated that this is because of the increased use of frozen meat, since freezing kills the tissue cysts, and better food hygiene in general (Forsgren M, Gille E, Ljungström I et al., Toxoplasma gondii in pregnant women in Stockholm in 1969, 1979, and 1987 [letter], Lancet 1991;337:1413–1414; Walker J, Nokes DJ, Jennings R, Longitudinal study of Toxoplasma seroprevalence in South Yorkshire, Epiemiol Infect 1992;108:99–106; Jones JL, Kruszon-Moran D, Sanders-Lewis K et al., Toxoplasma gondii infection in the United States, 1999–2004, decline from the prior decade, Am J Trop Med Hyg 2007;77:405–410). By contrast, there are no reports of a sharp decrease in the prevalence of schizophrenia in either the United States or Europe.