|
Toxoplasmosis-Schizophrenia Research
(last updated June 2010)
Welcome to the Toxo–Schizophrenia Research section. This site is maintained by the Stanley Medical Research Institute (SMRI), and the Stanley Laboratory of Developmental Neurovirology, for SMRI-funded and other researchers interested in the possible etiological relationship between Toxoplasma gondii (and related organisms) and schizophrenia (and related psychoses). The purpose of the webpage is to make information on this line of research, including background data and current research, easily available.
This section will be updated periodically. Comments, suggestions, additions, and corrections are welcomed. They can be sent to either E. Fuller Torrey, M.D. or Robert H. Yolken, M.D. .
Related sites:
www.toxodb.org/toxo This site provides detailed information on the genome of
Toxoplasma gondii.
www.schizophreniaforum.org This is a useful online forum to keep updated on schizophrenia
research.
TABLE OF CONTENTS
Introduction
I. All about Cats
II. Possible Transmission of T. gondii from Cats to Humans, Causing Schizophrenia
III. Epidemiological Similarities and Differences Between Toxoplasmosis and Schizophrenia
IV. Effects of T.gondii on Behavior and Psychiatric Symptoms
V. Studies of T.gondii Antibodies in Schizophrenia
VI. Neurotransmitters and T. gondii
VII. Neuropathology of T. gondii
VIII. Treatment Approaches
Introduction
SMRI has undertaken extensive research on infectious agents as one of the possible causes of schizophrenia. Among the infectious agents that appear most promising is Toxoplasma gondii, a protozoan parasite that causes toxoplasmosis and is carried by cats and other felines. Until recently, toxoplasmosis was thought to be a problem only for pregnant women who, if they become infected with T. gondii during their pregnancy, risk having the organism cause damage to the growing fetus. This is why pregnant women are advised to not change the litter in the cat litter box. Infections of children or adults by T. gondii were thought to be either asymptomatic or to cause an influenza-like or mononucleosis-like syndrome. It now seems possible that T. gondii may be associated with schizophrenia and perhaps other psychiatric syndromes.
Schizophrenia is a brain disease that begins in young adults, typically between the ages of 16 and 30, and is characterized by some combination of auditory hallucinations (hearing voices), delusions, flattened affect, disordered thought patterns, bizarre behavior, and social withdrawal. Schizophrenia affects approximately 1 percent of the adult population and in most cases is a lifelong disease with remissions and exacerbations. It is also a very expensive disease. Conservative estimates place the cost of schizophrenia in the United States at approximately $40 billion, including $10 billion in federal disability (SSI and SSDI) costs.
For additional information on schizophrenia, see Torrey EF, Surviving Schizophrenia, 5th edition (New York, HarperCollins, 2006) and the following websites:
www.schizophrenia.com
www.mentalhealth.com
www.chovil.com
I. All about Cats
Since felines are the definitive host of T. gondii, it is useful to know about them.
• Origin, domestication, and early history
About 12 million years ago, “the felid family underwent an explosive diversification, giving rise to thirty-seven species that today cover the earth’s geographical and ecological spectrum” (Burdiansky S, The Character of Cats, New York, Viking, 2002, p. 6). One of these species was Felis sylvestris, indigenous to the Middle East, East Asia, and Europe, and the predecessor of all domestic cats.
Cats were initially domesticated in Turkey, part of the Fertile Crescent, approximately 10,000 years ago, at the time farming was beginning (Driscoll CA, Menotti-Raymond M, Roca AL et al., The Near Eastern origin of cat domestication, Science 2007;317:519–523). It is likely that wild cats were attracted by the mice that accompanied the collections of grain. Given cat behavior as we know it, it also seems likely that cats domesticated themselves rather than being domesticated by humans.
From the beginning, cats were very useful to people in protecting grain and other food supplies, and they continued to be so in this role until recent years. For example, in 1850 a gold miner in California wrote: “This evening old Coe came up with our wagons and brought us a cat. Never were cats in such demand. . . . The whole town is overrun with mice, and they destroy a deal of property for us. . . . We were at once offered an ounce of gold dust for every pound the cat weighed” (Bretnor R, Bring cats, The American West, 1978;15:34).
For most of the time from when cats were initially domesticated 10,000 years ago until the end of the 18th century CE, cats were regarded almost exclusively as utilitarian creatures, specifically to kill mice and rats and thus protect food supplies. There are suggestions that occasionally they were regarded as pets, but except for ancient Egypt, such examples are rare. For example, in a burial in Cyprus dated to 9,500 years ago, a human and cat were buried together.
The major example of cats being regarded as pets was in ancient Egypt when, approximately 3,500 years ago (1,500 BCE), a local cult of worshipping a cat goddess (Bastet) became widespread. Cats were highly valued and often mummified when they died. Herodotus noted the Egyptian fondness for cats when he visited in 450 BCE. The Egyptians attempted to restrict the distribution of cats to other countries and prohibited their export.
The Greeks and Romans kept some cats as mousers, but there is no evidence that pet-keeping was widespread. Some historians claim that ferrets were used more commonly than cats to protect the grain. The Romans are thought to have introduced cats to central and western Europe, including Britain. Cats are thought to have reached India approximately 2,200 years ago (200 BCE) and to have reached China and Japan even later. As trade by shipping became common, cats became essential items on ships to keep the mice, and later rats, under control, and in this manner cats became geographically disseminated. References to cats as companions or pets are rare, and “up until the tenth century the cat is viewed, if not with respect, then with tolerance and as a necessity and asset to the household” (Lynnlee JL, Purrrfection: The Cat, West Chester, Pa., Schiffer, 1990, p. 21).
• Modern History
Beginning in the 11th century, tolerance for cats began to decrease in Europe for religious reasons, and “by the 13th century the church viewed witches as real and cats as instruments of the devil” (Lynnlee, p. 20). Dante (1265–1321), for example, mentioned cats only once in his work and compared them to demons. From the 14th century well into the 18th century, cats were regularly killed on specific religious holidays. “By the late 15th century the persecution of cats and witches was a mainstay of European society. . . . The 15th and 16th centuries are almost devoid of any cat literature and art. . . . During this period the cat still was used to control rodents, but it was rarely seen as a pet, for if so its existence and that of its owner were in jeopardy” (Lynnlee, p. 21). Cats became especially associated with heretical religious sects, such as the Waldensians and Manichaeans, and members of these sects were accused of worshipping the Devil in the form of a
black cat.
On feast days all over Europe, as a symbolic means of driving out the Devil, they were captured and tortured, tossed onto bonfires, set alight and chased through the streets, impaled on spits and roasted alive, burned at the stake, plunged into boiling water, whipped to death, and hurled from the tops of tall buildings, all in an atmosphere of extreme festive merriment. (Serpell JA, The domestication and history of the cat, in Turner DC and Bateson P, eds., The Domestic Cat, Cambridge, Cambridge University Press, 1988, p. 156).
At Metz, for example, on “cat Wednesday” during Lent, 13 cats were placed in an iron cage and publicly burned; this ritual took place each year from 1344 to 1777 (Kete K, The Beast in the Boudoir, Berkeley: University of California Press, 1994, p. 119).
The rehabilitation of cats began in the 18th century, driven by three things. First was a decline in the belief in witches. Second was the invasion of Europe by the brown (or gray) rat, which replaced the black rat and was more prolific and difficult to control. The brown rat reached Germany in 1753, Sweden in 1762, and Switzerland in 1808. Its multiplication was facilitated by increasing urbanization and its distribution facilitated by increasing sea travel. Cats were increasingly valued in urban areas and on shipboard. “Many administrative authorities began to set aside a special budget for the breeding and maintenance of ratting cats in museums, libraries, prisons, barracks, warehouses and stores” (Mery F, The Life, History and Magic of the Cats, London, Paul Hamlyn, 1967, pp. 56, 59). Finally, as Pasteur’s work and microbes became well known, disease became associated with being dirty, and the cat, by virtue of its cleanliness, was increasingly associated with health.
The earliest modern examples of keeping cats as pets occurred in the mid-18th century, first in Paris and later in London, among artists and writers. Cats became associated with intellectuals. By the early 19th century, descriptions can be found of children playing with cats. Cats began to be used in advertising in the 1850s, and “some cats were seen on paper fans, matchbooks, bookmarkers, and the like” (Lynnlee, p. 28). By the 1870s, interest in cats as pets had become so widespread that writers referred to it as a “cat fever,” “cat cult,” “cat fancy,” or “cat craze,” e.g. “Of late years there has been a rapid and promising growth of what disaffected and alliterative critics call the ‘cat cult,’ and poets and painters vie with on another in celebrating the charms of this long-neglected pet” (Repplier AQ, Agrippina, Atlantic Monthly, 1892;69:760). The first cat show in London took place in the Crystal Palace in 1871; the first show in New York was in Madison Square Garden in 1894.
• Distribution and numbers
As the British colonized the world in the 19th century, they took their cats with them and thereby introduced cats to Canada, Australia, and New Zealand. In 1857 in a popular journal, it was noted that “cats have increased the excitement caused by the arrival of our modern missionaries amongst an isolated and untaught people” (Anonymous, The cat, Household Words, 1857;15:370). In India cats became popular only among members of the upper castes who wished to emulate the British. In many other countries, cats were relatively uncommon and, if they appeared, were regarded as a source of protein rather than as pets. For example, in 1872 “the enormous amount of rats and scarcity of cats” was noted in West Africa (Anonymous, Cats, Chamber’s Journal, 1872;49:178).
Following World War II, cats became very widely distributed around the world, even in the Arctic. Among five Eskimo villages in Alaska north of the Arctic Circle, 8 percent of families owned a pet cat in 1974. Among Skolt Lapps in northern Finland, it was said in 1979 that “practically each family had at least one cat” (Peterson DR, Cooney MK, Beasley RP, Prevalence of antibody to Toxoplasma among Alaskan natives: relation to exposure to the felidae, J Infect Dis 1974;130:557–563; Huldt G, Lagercrantz R, Sheehe PR, On the epidemiology of human toxoplasmosis in Scandinavia especially in children, Acta Paediatr Scand 1979;68:745–749).
In recent years, several cities have been said to be heavily infested with cats. Stockholm has been called the “cat capital of the world,” and Paris is also said to have large numbers. In the Middle East, Istanbul, Damascus, and especially Cairo are also said to have many cats, the latter even having a “cat garden,” originally created by a 13th-century sultan.
Counting cats is notoriously difficult. In the United States, it has been estimated that there are approximately 78 million pet cats, which are found in one-third of all households, and an additional 73 million feral cats, thus totaling 151 million. Britain is said to have about 8 million cats, and Australia to have 20 million, one for every person (Will G, Millions and millions of cats, Washington Post, July 13, 1997). It is well known that, left unchecked, cats reproduce rapidly; “a pair of breeding cats and their offspring can exponentially produce over 400,000 cats in seven years” (Kelson L, The race to outpace feral cat overpopulation, Animal Guardian 1998;4:8).
• Cat feces
Cats excrete the oocysts of T. gondii in their feces for two to three weeks when they first become infected, usually as kittens or young cats. At any given time, it has been estimated that approximately 1 percent of cats are excreting T. gondii oocysts. One study claimed that “cats can shed as many as 500 million oocysts” during their initial infection (Dubey JP, Jones JL, Toxoplasma gondii infection in humans and animals in the United States, Int J Parasitol 2008;38:1257–1278). Another recent study of three communities in California with 12,244 total households reported 7,284 owned and 2,046 feral cats. The annual fecal deposition of these 9,330 cats in the three communities was estimated to be 106 tons of feces (Dabritz HA, Atwill ER, Gardner IA et al., Outdoor fecal deposition by free-roaming cats and attitudes of cat owners and nonowners toward stray pets, wildlife, and water pollution, J Am Vet Med Assoc 2006;229:74–81).
These same researchers calculated the fecal burden by square foot of soil in another California study. It is known that infected cats can excrete up to 20 million T. gondii oocysts each day during the period they are infected and that each oocyst can remain viable for a year or longer under proper climate conditions. Assuming that cats defecated in a completely random manner, the researchers calculated that each square foot of ground in these communities would be burdened with between 9 and 434 infected T. gondii oocysts each year (Dabritz et al.). Cats, of course, do not defecate randomly but favor specific outdoor spots, meaning that such spots are inevitably burdened with a very large number of oocysts (Afonso E, Lemoine M, Poulle M-L et al., Spatial distribution of soil contamination by Toxoplasma gondii in relation to cat defecation behaviour in an urban area, Int J Parasitol 2008;38:1017–1023).
• Transmission of T. gondii to humans
T. gondii can be transmitted to humans in one of two ways. This can occur at any time in life, including while in utero if the pregnant woman becomes infected.
A. As tissue cysts in the muscle of infected animals
The infection of mammals with T. gondii is widespread. Such infections occur when farm animals ingest feed containing cat feces; when grazing animals inhale or ingest dried cat feces deposited on the ground; and when an animal eats a smaller animal, such as a mouse or rat that is infected. T. gondii then invades many parts of the body, especially muscles, where it becomes tissue cysts and remains for life. When the muscle is eaten as meat, especially if it has not been thoroughly cooked, the person becomes infected.
Lamb and pork are thought to be the most common source of T. gondii tissue cysts for humans, although cysts also occur in beef, chicken, and wild animal meat (e.g., deer, moose, bear). There have even been epidemics of adult toxoplasmosis among individuals who ate undercooked meat, such as hamburger, from a common source (Kean BH, Kimball AC, Christenson WN. An epidemic of acute toxoplasmosis. JAMA 1969;208;1002–1004).
B. As oocysts directly from the feces of infected cats
As previously noted, approximately 1.5 million cats (1 percent of 150 million) in the United States are excreting oocysts on any given day; they may excrete up to 20 million oocysts per day, and the oocysts may live for a year or longer. Thus, wherever cats defecate is likely to be a source of contamination. Children’s play areas and sandboxes are common places for cats to defecate because they can use the area’s loose soil or sand to bury their feces. Children may become infected by putting dirty hands, including oocysts, in their mouths. A family epidemic was described as having occurred this way (Stagno S, Dykes AC, Amos CS et al. An outbreak of toxoplasmosis linked to cats. Pediatrics 1980;65:758–762, copyright 1980, the American Academy of Pediatrics; linked to PDF file with permission).
As the cat feces dry, the oocysts may become aerosolized. They can thus be inhaled by a person changing cat litter or just walking in an area where cats have defecated. An outbreak of toxoplasmosis among patrons of a riding stable was thought to have occurred in this manner (Teutsch SM, Juranek DD, Sulzer A et al. Epidemic toxoplasmosis associated with infected cats. N Engl J Med 1979;300:695–699).
Sandboxes (also called sandpits) are of special interest. Studies of sandboxes in public parks have been carried out in Japan. In one study, 12 of the 13 sandboxes were contaminated with animal feces; the “mean number of feces found in 1 square meter of the sandpits was 35” (Uga S, Prevalence of Toxocara eggs and number of faecal deposits from dogs and cats in sandpits of public parks in Japan, J Helminthol 1993;67:78–82). In another study of three public sandboxes observed over 140 days, an average of 2.3 cat defecations occurred each day in each sandbox (Uga S, Minami T, Nagata K. Defecation habits of cats and dogs and contamination by Toxocara eggs in public park sandpits. Am J Trop Med Hyg 1996;54:122–126).
Assuming that 1 percent of the cats were infected, that each infected cat excreted 10 million oocysts each time it defecated, and that the oocysts remained viable for one year, each sandbox would contain approximately 85 million viable oocysts at any given time. For children playing in such a sandbox, the chances of inhaling or ingesting (e.g., by putting fingers in mouth) T. gondii oocysts would appear to be high.
Gardens are also commonly used by cats for defecation and are also thought to be a common source of infection by inhalation for gardeners. Unwashed vegetables from gardens can also carry oocysts. Studies have also shown that cockroaches and flies can carry oocysts from cat feces to fruits and vegetables (Wallace GD, Experimental transmission of Toxoplasma gondii by cockroaches, J Infect Dis 1972;126:545–547; Wallace GD, Experimental transmission of Toxoplasma gondii by filth-flies, Am J Trop Med Hyg 1971;20:411–413). Another possible mode of transmission is by dogs that roll in cat feces. One study reported that 23 percent of dogs did this, suggesting “the contamination of fur, after rolling in cat feces containing oocysts, might make these accessible to children who pet dogs” (Frenkel JK, Parker BB, An apparent role of dogs in the transmission of Toxoplasma gondii: the probable importance of xenosmophilia, Ann NY Acad Sci 1996;791:402–407).
Finally, water infected with T. gondii oocysts is increasingly suspected of being a major source of transmission (Dubey JP, Toxoplasmosis—a waterborne zoonosis, Vet Parisit 2004;126:57–72). The water is thought to become contaminated by runoff from areas where cats defecate. Several epidemics of toxoplasmosis have been reported due to contaminated water, most notably a 1995 epidemic in Victoria, British Columbia, due to the contamination of the city water supply by cat feces (Bowie WR, King AS, Werker DH et al. Outbreak of toxoplasmosis associated with municipal drinking water. Lancet 1997;350:173–177, copyright 1997; linked to PDF file with permission from Elsevier).
The relative importance of different modes of T. gondii transmission has been widely debated but minimally studied. In countries like France, which has a high rate of T. gondii-infected individuals, the most important source of transmission is thought to be undercooked meat. Studies of pregnant women in Europe have identified the eating of raw or undercooked meat as the most likely source of transmission (Kapperud G, Jenum PA, Stray-Pedersen B et al., Risk factors for Toxoplasma gondii infection in pregnancy: results of a prospective case-control study in Norway, Am J Epidemiology 1996;144:405–412; Baril L, Ancelle T, Goulet V et al., Risk factors for Toxoplasma infection in pregnancy: a case-control study in France, Scand J Infect Dis 1999;31:305–309; Cook AJC, Gilbert RE, Buffolano W et al., Sources of toxoplasma infection in pregnant women: European multicentre case-control study, Br Med J 2000;321:142–147). In countries like the United States, in which meat is generally well cooked, direct transmission from cats is thought to be more important.
The question has been raised whether the clinical outcome is different if a human becomes infected by a tissue cyst or an oocyst. In mice, infection by oocysts appears to be more pathogenic. In humans, “circumstantial evidence suggests that oocyst-induced infections . . . are clinically more severe than tissue cyst-acquired infections” (Dubey JP, Toxoplasmosis—a waterborne zoonosis, Vet Parisit 2004;126:57–72). There are also suggestions that reinfection can occur with different strains of T. gondii (Elbez-Rubinstein A, Ajzenberg D, Dardé M-L et al., Congenital toxoplasmosis and reinfection during pregnancy: case report, strain characterization, experimental model of reinfection, and review, J Infect Dis 2009;199:280–285).
II. Possible Transmission of T. gondii from Cats to Humans, Causing Schizophrenia
As noted previously, T. gondii can be transmitted from cats to humans in many different ways, some of which require no contact whatever between cats and humans, e.g., through tissue cysts in undercooked lamb, drinking water infected with oocysts, oocysts deposited by a neighborhood cat in your garden. For this reason, attempts to show a correlation between having antibodies to T. gondii and past contact with cats have yielded very inconsistent results.
A review of 30 such studies reported that half of them found a correlation, but half did not (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. 85–91). Those studies that were negative were more likely to have been studies of adults, e.g., pregnant women who were asked if they presently owned a cat. Those studies that were positive were more likely to have included children and teenagers, such as studies done in Costa Rica and Panama (Sousa OE, Saenz RD, Frenkel JK, Toxoplasmosis in Panama: a 10-year study, Am J Trop Med Hyg 1988;38:315–322; Frenkel JK, Ruiz A, Human toxoplasmosis and cat contact in Costa Rica, Am J Trop Med Hyg 1980;29:1167–1180). The results varied depending on how the question was asked, with cat ownership in childhood more likely to yield a positive correlation with T. gondii antibodies than cat ownership in adulthood. The complexity of studying human–cat contact was also illustrated by a Norwegian study that asked about cat contact in great detail. Becoming infected with T. gondii was not statistically related to “living in a neighborhood with a cat” (p=0.71) or “living in a household with a cat” (p=0.13) but was statistically significantly related to “living in a household with a kitten less than 1 year old” (p=0.04) (Kapperud G, Jenum PA, Stray-Pedersen et al., Risk factors for Toxoplasma gondii infection in pregnancy: results of a prospective case-control study in Norway, Am J Epidemiol 1966;144:405–412).
In view of the above, it is of interest that two studies that have assessed cat contact during childhood reported that it was significantly more common in individuals with schizophrenia than in controls. In the first study of 165 parents of individuals with schizophrenia and bipolar disorder, 51 percent reported that they owned a cat during pregnancy or during the first 10 years of life of the affected individuals, compared to 38 percent among matched controls (p=0.02, chi square; however, this was not corrected for the number of questions asked, which would require a p<0.01 using a Bonferroni correction). The question was asked for four different periods, and the results were as follows:
|
Owned cat |
|
|
During pregnancy |
Birth to 1 yr |
1–5 yrs |
6–10 yrs |
|
Subjects |
18% |
16% |
29% |
43% |
|
Controls |
13% |
15% |
28% |
34% |
Thus, the largest difference in the ages for cat ownership was for ages 6–10. Dog or other pet ownership was not included in this questionnaire (Torrey EF, Yolken RH, Could schizophrenia be a viral zoonosis transmitted from house cats, Schizophr Bull 1995;21:167–171).
The second study included 264 mothers of individuals with schizophrenia or bipolar disorder and 528 matched controls and included questions on both cat and dog ownership as follows:
|
|
Owned cat |
Owned dog |
|
|
During pregnancy |
Birth to age 13 |
During pregnancy |
Birth to age 13 |
|
Subjects |
17% |
52% |
31% |
73% |
|
Controls |
16% |
42% |
39% |
78% |
Families in which the individual later developed schizophrenia or bipolar disorder were significantly more likely to have owned a cat, but not a dog, between birth and age 13 (p=0.0072) but not during the pregnancy (Torrey EF, Rawlings R, Yolken RH, The antecedents of psychoses: a case-control study of selected risk factors, Schizophr Res 2000;46:17–23).
Given the mixed results of previous studies of antibodies to T. gondii and history of cat contact, the results of these two studies suggest that if T. gondii is associated etiologically with some cases of schizophrenia, then transmission of the protozoa is most likely to be via oocysts, not tissue cysts, and to take place during childhood.
Current SMRI-funded research in this area
In association with other SMRI-funded research studies, cat contact in individuals with schizophrenia is being assessed in studies in the United States (Dickerson et al.); Ethiopia (Shibre et al.); Germany (Bachmann et al.); and China (Wang et al.). Another study of this relationship is underway in Czechoslovakia (Flegr et al.).
III. Epidemiological Similarities and Differences Between Toxoplasmosis and Schizophrenia
Epidemiologically, there are at least eight 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).
• Seasonal variation
Individuals who develop schizophrenia are more likely to be born in the winter and early spring months. This pattern has been confirmed in over 100 studies in both the northern and southern hemispheres. The schizophrenia birth excess is 5-8 percent and is more marked in colder than warmer states in the U.S. (Torrey EF, Torrey BB, Peterson MR, Seasonality of schizophrenic births in the United States, Arch Gen Psychiatry 1977;34:1065-1070) and in colder than warmer countries in Europe (Torrey EF, Miller J, Rawlings R et al., Seasonality of births in schizophrenia and bipolar disorder: a review of the literature, Schizophr Res 1997;28:1–38). In addition to having a winter and early spring excess of births, individuals who later develop schizophrenia have a fall deficit of births that is as statistically significant as their winter-spring excess.
Six studies of the seasonality of toxoplasmosis have been carried out. Two studies assessed the acquisition of antibodies to T. gondii in large numbers of pregnant women in Slovenia (Logar J, Soba B, Premru-Srsen et al., Seasonal variations in acute toxoplasmosis in Slovenia, Clin Microbiol Infect 2005;11:852-855) and Austria (Sagel U, Mikolajczyk RT, Kramer A, Seasonal trends in acute toxoplasmosis in pregnancy in the federal state of Upper Austria, Clin Microbiol Infect 2010;16:515-517); both studies reported a twofold increase in seroconversion in winter months compared to summer months. A study in the Netherlands looked retrospectively at the birth months of 532 patients with ocular toxoplasmosis and reported a significant increase in May (with assumed seroconversion in March, April, and May) and a significant deficit in November (Meenken C, Rothova A, Kijlstra A et al., Seasonal variation in congenital toxoplasmosis [letter], Br J Ophthalmol 1991;75;639).
Three studies looked at the seasonality of receipt of lab specimens for testing for T. gondii. Almost all were cases of suspected ocular toxoplasmosis or toxoplasmic lymphadenitis. Such studies are an indication of the clinical manifestations of toxoplasmosis but not when the affected individuals were born. A UK study reported a peak in such lab reports from November to February (winter), with a deficit in September (Bannister B, Toxoplasmosis 1976-80: review of laboratory reports to the Communicable Disease Surveillance Centre, J Infect 1982;5:301-306), but another UK study reported no seasonal pattern (Ryan M, Hall SM, Barrett NJ et al., Toxoplasmosis in England and Wales 1981 to 1992, CDR Review: Communicable Disease Report 1995;5:R13-22). Finally, a similar study of lab reports in Canada reported a relatively even distribution of reports for all months except September-November, when there was a deficit (Tizard IR, Fish NA, Quinn JP, Some observations on the epidemiology of toxoplasmosis in Canada, J Hyg Camb 1976;77:11-21).
Thus, it appears that human T. gondii infections occur more commonly in the winter months, with a deficit in the fall months. This coincides with the seasonal pattern of individuals who develop schizophrenia. Given the multitude of ways in which T. gondii can be acquired in humans, how might the two be linked? One possibility is as a consequence of cats spending more time in homes in winter months than in summer months. Infected cats would thus be excreting their oocysts into the home environment during those months, thus potentially infecting a woman in the last months of pregnancy and/or a newborn child. This might also explain why schizophrenia birth seasonality is more pronounced in colder states and colder countries, where cats are more likely to be indoors.
Another possibility is that infection with T. gondii and schizophrenia might be linked through the seasonality of cat births. Cats are born throughout the year, but in the U.S. cat births peaked in March-August in one study (Reif JS, Seasonality, natality and herd immunity in feline panleukopenia, Am J Epidemiol 1976;103:81-87) and in March-May in another study (Nutter FB, Levine JF, Stoskopf MK, Reproductive capacity of free-roaming domestic cats and kitten survival rate, J Am Vet Med Assoc 2004;225:1399-1402). Cats most commonly become initially infected with T. gondii as kittens, when they first start hunting, which is usually 6-10 weeks after being born. It is during the approximately 2 weeks when they are initially infected that they excrete oocysts and thus may infect humans. The peak months when kittens are born, March-May, could thus produce May-July as the months during which the newborn kittens would be most likely to be infective. This does not correspond with the peak births of individuals with schizophrenia; thus, this explanation seems less likely. A May-July peak of infectious kittens would correspond with the first trimester of pregnancy for women giving birth in the winter months, but these women would be expected to give birth to offspring who have the congenital toxoplasmosis syndrome.
• 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.
IV. Effects of T. gondii on Behavior and Psychiatric Symptoms
• Early research
Beginning in the late 1970s, G. Piekarski (1978) and P.-A. Witting (1979) in Bonn began investigations to ascertain possible effects of latent T. gondii on mice and rats. The impetus for their research appears to have been the reported behavioral effects of other parasitic infections and the known association of congenital T. gondii with mental retardation. Piekarski and Witting reported that T. gondii caused impaired learning in mice and rats and impaired memory in mice. Based on these findings, Hutchinson, Hay et al. in Glasgow studied T. gondii–infected mice and reported that, compared to uninfected controls, the infected mice had increased activity, especially in exploring novel environments. Holliman summarized this early research (Holliman RE, Toxoplasmosis, behaviour and personality, J Infect 1997;35:105–110).
• Behavioral manipulation by T. gondii in rodents
The manipulation hypothesis states that a parasite may alter the behavior of its host in order to improve its transmission rate. Carl Zimmer’s Parasite Rex provides wonderful illustrations of this phenomenon.
Joanne Webster (SMRI grantee) and her colleagues, initially at Oxford and now at Imperial College London, noted the early research cited above and carried it forward. Beginning in 1994, they published a series of studies demonstrating that rats infected with T. gondii were more active and less neophobic of cat urine than controls rats (Berdoy M, Webster JP, Macdonald DW, Fatal attraction in rats infected with Toxoplasma gondii, Proc R Soc Lond B 2000;267:1591–1594). Both changes would make it more likely that the rat would be eaten by a cat, thus completing the life cycle of T. gondii and being an example of the manipulation hypothesis. These studies were summarized by Dr. Webster (Webster JP, Rats, cats, people and parasites: the impact of latent toxoplasmosis on behaviour, Microbes Infect 2001;3:1037–1045).
Given the findings of Webster et al., Ajai Vyas (SMRI grantee) and his colleagues at Stanford University sought to replicate them. They did so, showing in both mice and rats that T. gondii infection reverses the rodents’ natural aversion to the smell of cat urine and causes them to instead “develop an actual attraction to the pheromones” (Vyas A, Kim S-K, Giacomini N et al., Behavioral changes induced by Toxoplasma infection of rodents are highly specific to aversion of cat odors, Proc Natl Acad Sci USA 2007;104:6442–6447, copyright 2007, the National Academy of Sciences of the USA; linked to PDF file with permission).
As suggested by the above findings, there is evidence that the effects of T. gondii on the brain are highly specific. For example, in experiments in which mice have been infected, the mice may have profound and widespread brain pathology and deficits in motor coordination and sensory deficits, but their cognitive skills remain relatively intact (Gulinello M, Acquarone M, Kim JH et al., Acquired infection with Toxoplasma gondii in adult mice results in sensorimotor deficits but normal cognitive behavior despite widespread brain pathology, Microbes Infect 2010; Mar 27, Epub ahead of print).
• Effects of T. gondii on personality traits of humans
Jaroslav Flegr (SMRI grantee) and his colleagues at Charles University in Prague have, since 1992, been studying the effects of T. gondii infection on human personality traits and behavior. Utilizing university students, military recruits, and blood donors, Flegr et al. have administered a series of personality questionnaires and compared individuals with and without antibodies to T. gondii. Infected men were shown to be more expedient, suspicious, jealous, and dogmatic, whereas infected women had more warmth and superego strength. Flegr has summarized these findings (Flegr J, Effects of Toxoplasma on human behavior, Schizophr Bull 2007;33:757–760).
• Effects of T. gondii on the behavior of humans
Flegr et al. also compared his infected and uninfected groups on reaction time as measured by a standard computerized test. Infected individuals performed significantly more poorly and appeared to lose their concentration more quickly (Havlicek J, Gasova Z, Smith AP et al., Decrease in psychomotor performance in subjects with latent ‘asymptomatic’ toxoplasmosis, Parasitology 2001;122:515–520).
Flegr et al. also compared the sera of 146 individuals deemed to have been responsible for causing a motor vehicle accident, with 446 controls. Those individuals who had antibodies to T. gondii, compared with those without antibodies, had more than twice the risk of having caused a motor vehicle accident (Flegr J, Havlicek J, Kodym P et al., Increased risk of traffic accidents in subjects with latent toxoplasmosis: a retrospective case-control study, BMC Infect Dis 2002;2:11).
In Turkey, Yereli et al. replicated the association between traffic accidents and T. gondii infection. In a case-control study, they compared 185 individuals “who were involved in a traffic accident while driving,” with 185 matched controls. T. gondii antibodies were found in 24 percent of those involved in traffic accidents, compared with 6 percent of the controls (p<0.05) (Yereli K, Balcioglu IC, Ozbilgin A, Is Toxoplasma gondii a potential risk for traffic accidents in Turkey? Forensic Sci Int 2006;163:34–37).
• Psychiatric manifestations of congenital T. gondii infections
It is clearly established that congenital infections with T. gondii, especially early in pregnancy, can produce intracranial calcifications, mental retardation, deafness, seizures, and retinal damage. Less clearly established are the long-term effects of congenital infection that occur late in pregnancy and that are often latent at birth. Two research groups have reported late effects, especially lower IQ, following latent congenital infections (Alford A, Stagno S, Reynolds DW, Congenital toxoplasmosis: clinical, laboratory, and therapeutic considerations, with special reference to subclinical disease, Bull NY Acad Med 1974;50:160–181; Wilson CB, Remington JS, Stagno S et al., Development of adverse sequelae in children born with subclinical congenital Toxoplasma infection, Pediatrics 1980;66:767–774). However, long-term follow-up of a similar cohort in Europe reported no loss of IQ or other significant sequelae (Koppe JG, Rothova A, Congenital toxoplasmosis: a long-term follow-up of 20 years, Int Ophthalmol 1989;13:387–390).
No study has reported psychosis or other symptoms of schizophrenia in children infected with congenital latent toxoplasmosis. However, a 30-year psychiatric follow-up of the European cohort cited above reported one case of major depression, one suicide, and one case of sex change among the eight cases on which clinical data were available (Selton J-P, Kahn RS, Schizophrenia after prenatal exposure to Toxomplasma gondii? Clin Infect Dis 2002;35:633–634).
• Psychiatric manifestations of adult T. gondii infections
Humans may become infected with T. gondii at any time in life. In immunocompetent individuals, the infection is asymptomatic 90 percent of the time. In the other 10 percent, the "primary infections cause a mild, mononucleosis-like illness with low-grade fever, malaise, headache, and cervical lymphadenopathy" (Kravetz JD, Toxoplasma gondii, in Fratamico PM, Smith JL, Brogden KA [eds], Sequelae and Long-Term Consequences of Infectious Diseases [Washington, D.C.: ASM Press, 2009], pp. 217–228). The clinical picture is nonspecific but often includes headache, fever, malaise, myalgia, and lymphadenopathy (Carme B, Demar M, Ajzenberg D et al., Severe acquired toxoplasmosis caused by wild cycle of Toxoplasma gondii, French Guiana, Emerg Infect Dis 2009;15:656-658; Silva CS, Neves ES, Benchimiol El et al., Postnatal acquired toxoplasmosis patients in an infectious disease reference center, Braz J Infect Dis 2008;12:438-441). In recent years, most clinical cases have been described in patients with AIDS, thus making it difficult to ascertain which clinical symptoms are due to the toxoplasmosis and which are due to AIDS. However, in 1966, prior the AIDS epidemic, two publications summarized the neurological and psychiatric symptoms found in T. gondii infection occurring in adults.
Kramer in the Netherlands summarized 114 cases of symptomatic adult toxoplasmosis published between 1940 and 1964. Among these, he noted that “psychiatric disturbances were very frequent,” occurring in 24 cases. Some cases were described as having acute or subacute psychosis, and others as having “psychic alteration” (Kramer W, Frontiers of neurological diagnosis in acquired toxoplasmosis, Psychiatr Neurol Neurochir 1966;69:43–64). Ladee et al., also in the Netherlands, noted that “the literature not infrequently focuses attention on psychoses with schizophrenic or schizophreniform features that accompany chronic toxoplasmosis or that acquired in childhood or early in adult life. . . . In several instances a neurasthenic prodromal stage is followed by an initially suspected paranoid or paranoid-hallucinatory picture” (Ladee GA, Scholten JM, Meyes FEP, Diagnostic problems in psychiatry with regard to acquired toxoplasmosis, Psychiatr Neurol Neurochir 1966;69:65–82).
Many of these early reported cases are very interesting. For example, in 1951 Ström reported two cases of adult toxoplasmosis in laboratory workers. A 22-year-old woman who “often pipetted toxoplasma exudates” developed lyphadenopathy, headache, and fever. Diagnosis of toxoplasmosis was confirmed by skin test. Attempts to demonstrate T. gondii by microscopy of CSF or inoculation of CSF into mice was unsuccessful. She also had psychiatric symptoms: three months after the onset of infection, she “finds it difficult to concentrate,” “cannot follow a conversation when several people are present,” and “she feels far away, as if her body wasn’t there” (Ström J, Toxoplasmosis due to laboratory infection in two adults, Acta Med Scand 1951;139:244–252).
In another case, a 47-year-old woman who also worked in the laboratory with T. gondii presented “obviously delirious with delusions and hallucinations . . . the patients was irrational, spoke frequently to imaginary characters in the room and indicated she was going to die from toxoplasmosis.” In fact, she went into a coma and did die, and her diagnosis was confirmed at autopsy by animal inoculation of brain, liver, and spleen. Despite a normal CSF (no cells, normal protein and sugar), it was also positive for T. gondii by animal inoculation (Sexton RC, Eyles DE, Dillman RE, Adult toxoplasmosis, Am J Med 1953;14:366–377).
Since 1966, there have been occasional similar case reports, but except for patients with AIDS in whom psychiatric symptoms are prominent, this subject has received little attention. An example of a case report was a 20-year-old male who presented with delusions, auditory hallucinations, and catatonic symptoms but was then diagnosed with toxoplasmic encephalitis based on serological tests (Freytag HW, Haas H, Psychiatric aspects of acquired toxoplasmosis, Nervenarzt 1979;50:128–131, in German). The incidence of such cases is unknown.
Another possible psychiatric manifestation of T. gondii infection in immunocompetent hosts is suicidal ideation. One study in the United States assessed T. gondii antibodies in 99 individuals who had made a suicide attempt; 119 individuals with a recurrent mood disorder but no history of suicide attempts; and 39 unaffected controls. There was no significant difference in T. gondii seropositivity, but those who had attempted suicide had higher T. gondii antibody titres (p = 0.004) (Arling TA, Yolken RH, Lapidus M et al., Toxoplasma gondii antibody titers and history of suicide attempts in patients with recurrent mood disorders, J Nerv Ment Dis 2009;197:905–908). The association between suicide attempts and higher titre to T. gondii antibodies was recently replicated by a study in Turkey (Yagmur F, Yazar S, Temel HO et al., May Toxoplasma gondii increase suicide attempt-preliminary results in Turkish subjects? Forensic Sci Int 2010; Mar 8, Epub ahead of print).
Another approach to this question is to do a follow-up examination of individuals who are thought to have been infected by T. gondii during outbreaks of water-borne infection. Examples of such outbreaks include a 1979 outbreak among 39 U.S. military personnel (Benenson MW, Takafuji ET, Lemon SM et al., Oocyst-transmitted toxoplasmosis associated with ingestion of contaminated water, N Engl J Med 1982;307:666–669) and a 1995 outbreak among an estimated 2,900–7,700 people in Victoria, Canada (Bowie WR, King AS, Werker DH et al., Outbreak of toxoplasmosis associated with municipal drinking water, Lancet 1997;350:173–177). To date, such follow-up studies have not been done.
In view of recent research, it now seems likely that the different strains of T. gondii produce different clinical outcomes. Although it has been known that type I T. gondii is much more lethal in mice than type II or type III, it was not known whether or not this also applies to human infections. A recent study from our laboratory suggests that type I T. gondii, compared to type II or III, is more likely to produce psychotic symptoms, especially for affective psychoses (Xiao J, Buka SL, Cannon TD et al., Serological pattern consistent with infection with type I Toxoplasma gondii in mothers and risk of psychosis among adult offspring, Microbes Infect 2009;11:1011–1018).
V. Studies of T. gondii Antibodies in Schizophrenia
§ Studies of antibodies in individuals who have schizophrenia
The first study of antibodies against T. gondii carried out on individuals with psychoses was done by Kozar in Poland in 1953 using a skin test. This was followed by other studies in East Germany in 1956, Czechoslovakia in 1957, Bulgaria in 1962, and Russia in 1962. In the early 1980s, Chinese researchers became aware of this research and subsequently became the leading researchers on the prevalence of T. gondii antibodies in schizophrenia.
Since Kozar’s original study, there have been at least 54 similar studies. A 2007 review of 42 of these studies included a meta-analysis of 23 of them in which the odds ratio of having T. gondii antibodies with a diagnosis of schizophrenia was OR 2.73. In other words, if a person has been infected with T. gondii, he/she has a 2.7 times greater chance of having schizophrenia than if the person had not been infected (Torrey EF, Bartko JJ, Lun Z-R et al., Antibodies to Toxoplasma gondii in patients with schizophrenia: a meta-analysis, Schizophr Bull 2007;33:729–736).
Since the publication of this review, at least 12 other studies have been completed. Of the 54 total studies, all except 5 reported that the individuals with schizophrenia and other psychoses had a higher prevalence of antibodies to T. gondii than the controls.
§ Studies of antibodies in individuals prior to the onset of schizophrenia
In a study of military personnel, serum specimens were available from periods of up to 11 years prior to the onset of schizophrenia. The serum of 180 individuals with schizophrenia and 532 matched (3:1) controls were assessed for IgG antibodies to T. gondii and other infectious agents. Among those with schizophrenia, significantly increased levels of antibodies were seen prior to the onset of illness (hazard ratio = 1.24, p<0.01), maximal in the 6 months prior to onset but seen as early as 3 years prior to the onset (Niebuhr DW, Millikan AM, Cowan DN et al., Selected infectious agents and risk of schizophrenia among U.S. military personnel, Am J Psychiatry 2008;165:99–106).
In another study, antibodies against T. gondii were assessed in 105 young individuals who were thought to be at “ultra-high risk” for developing schizophrenia because of their early symptoms and behavior. Among the 105, 18 had antibodies to T. gondii, and “being Toxoplasma-positive was significantly associated with more severe positive psychotic symptoms, and more severe psychiatric symptoms in general” (Amminger GP, McGorry PD, Berger GE et al., Antibodies to infectious agents in individuals at ultra-high risk for psychosis, Biol Psychiatry 2007;61:1215–1217).
§ Studies of antibodies in newborn children who later develop schizophrenia
In Denmark, Mortensen et al. obtained sera (from blood collected for PKU analysis) on 71 individuals who developed schizophrenia prior to age 18 (early-onset cases) and matched controls (2:1). T. gondii IgG antibodies were increased in cases compared to controls (p=0.045; OR=1.79) (Mortensen PB, Nørgaard-Pedersen B, Waltoft BL et al., Toxoplasma gondii as a risk factor for early-onset schizophrenia: analysis of filter paper blood samples obtained at birth, Biol Psychiatry 2007;61:688–693).
§ Studies of antibodies in maternal sera from late in pregnancy
Brown et al. assessed antibodies to T. gondii in 63 women who gave birth to individuals (cases) who later developed schizophrenia, schizoaffective disorder, or schizophrenia spectrum disorders. They used 123 matched controls. Among the cases, the incidence of high IgG antibody titres was significantly increased (p=0.051; OR 2.61) (Brown AS, Schaefer CA, Quesenberry CP et al., Maternal exposure to toxoplasmosis and risk of schizophrenia in adult offspring, Am J Psychiatry 2005;162:767–773).
§ Do antibodies to T. gondii remain detectable over many years?
It has been widely assumed that once a person is exposed to T. gondii they will remain antibody-positive for life. However, no long-term study has been done on this question in humans. In 1941, Dr. Albert Sabin reported that in his experiments on monkeys, “it has been observed that convalescent monkeys may lose their antibodies as early as six weeks after infection” (Sabin AB, Toxoplasmic encephalitis in children, JAMA 1941;116:801–807). There are also suggestions from human studies that seropositivity is not lifelong; in one study, the mean duration of seropositivity was 40 years (Van Druten H, Van Knapen F, Reintjes A, Epiemiologic implications of limited-duration seropositivity after toxoplasma infection, Am J Epidemiol 1990;132:169–180).
Current SMRI-funded research in this area
§ David Niebuhr et al., Walter Reed Army Institute of Research. Enlarged sample of sera from military personnel with schizophrenia and matched controls.
§ Preben Mortensen et al., University of Aarhus, Denmark. Enlarged sample of sera samples from newborn children.
§ Huiling Wang et al., University of Wuhan, China. Antibody studies of university students who develop schizophrenia, with serum collected when they begin university, prior to the onset of their illness.
§ Faith Dickerson et al., Sheppard Pratt Hospital. T. gondii antibodies in individuals with first-episode schizophrenia.
§ Silke Bachmann et al., University of Halle, Germany. T. gondii antibodies in individuals with first-episode schizophrenia.
§ Steven Buka, Brown University, et al. Antibody studies of third-trimester sera of mothers who gave birth to children who developed schizophrenia and analysis of T. gondii strain differences.
§ Yasuhiro Suzuki et al., University of Kentucky. Analysis of T. gondii antigens recognized by IgG antibodies to tachyzoites, but not bradyzoites, in the brain.
VI. Neurotransmitters and T. gondii
For more than 40 years, it has been known that neurotransmitters are involved in the pathogenesis of schizophrenia. An excess of dopamine has been widely suspected, and along with genetics, dopamine-excess has been one of the most thoroughly researched theories. Despite hundreds of research projects, however, relatively few abnormalities in the dopamine system have ever been identified in individuals with schizophrenia. In recent years, more research attention has been focused on other neurotransmitters, especially glutamate and GABA.
§ Origin of interest in dopamine and T. gondii
The origin of interest in dopamine and T. gondii appears to have been the 1985 paper by Henry H. Stibbs, Ph.D., 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 level by 34 percent in infected rats (Stibbs HH, Neurochemical and activity changes in rats infected with Trypanosoma brucei gambiense, J Parasitology 1984;70:428–432). 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 5 weeks (= chronic group). Ten control mice were also killed at 5 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 HH, Changes in brain concentrations of catecholamines and indoleamines in Toxoplasma gondii infected mice, Ann Trop Med Parasitol 1985;79:153–157, copyright1985, Maney Publishing, www.maney.co.uk/journals/atmp; linked to PDF file with permission).
§ Toxoplasma gondii has the ability to make dopamine
In 2009, Dr. Glenn McConkey and his colleagues at the University of Leeds in the UK demonstrated that T. gondii has the genes encoding two critical enzymes needed to make dopamine. It has the gene for phenylalananine hydroxylase, which changes phenylalanine to tyrosine, and also the gene for tyrosine hydroxylase, which changes tyrosine to dopa, the precursor of dopamine. These genes were not found in any other closely related parasites except Neospora. This finding suggests the possibility that the excess dopamine thought to occur in individuals with schizophrenia might be being introduced by T. gondii rather than made by the affected individuals (Gaskell EA, Smith JE, Pinney JW et al., A unique dual activity amino acid hydroxylase in Toxoplasma gondii, PLoS ONE 2009;4:e4801).
§ Effects of changing levels of dopamine on behavior induced by T. gondii infection
Joanne Webster (SMRI grantee) 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 JP, Lamberton PHL, Donnelly CA et al., 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 R Soc B 2006;273:1023–1030, copyright 2006, the Royal Society; linked to PDF file with permission).
Jaroslav Flegr (SMRI grantee) 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 A, Kodym P, Frynta D et al., The role of dopamine in Toxoplasma-induced behavioural alterations in mice: an etiological and ethnopharmacological study, Parasitology 2006;133:525–535).
In other publications, Flegr et al. have speculated that dopamine is the “missing link between schizophrenia and toxoplamosis,” specifically suggesting that dopamine is increased by activated cytokines (e.g., IL–2) as a consequence of infection (Flegr J, Preiss M, Klose J et al., 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;63:253–268; Flegr J, Effects of Toxoplasma on human behavior, Schizophr Bull 2007;33:757–760).
Current SMRI-funded research in this area
§ Robert Sapolsky et al., Stanford University. The effects of Toxoplasma gondii on dopaminergic brain systems.
§ Glenn McConkey and Joanne Webster, University of Leeds and Imperial College London. Role of L-DOPA synthesis by Toxoplasma gondii on host behavior.
VII. Neuropathology of T. gondii
The neuropathology of schizophrenia is subtle, with mild atrophy and dilated ventricles. The brain regions of greatest interest have been the prefrontal cortex, hippocampus, and association cortex, which
includes the superior temporal gyrus and inferior parietal lobule;
other areas, such as the cingulate, basal ganglia, thalamus, and
cerebellum, are also thought to be involved. Abnormalities have been
described in both neurons and glia.
The neuropathology of congenital toxoplasmosis has been well described. It consists of periaqueductal and periventricular vasculitis with necrosis. Obstruction of the aqueduct may produce hydrocephalis and the necrotic tissue may calcify (Frenkel JK, Pathology and pathogenesis of congenital toxoplasmosis, Bull NY Acad Med 1974;50;182–191).
The neuropathology of T. gondii infection acquired after birth has been less completely described except for cases of immunosuppression, such as AIDS. In one of the few cases reported, a 6-year-old boy died from acute toxoplasma encephalitis and was autopsied one hour after death. According to the report, “there was no gross pathologic change . . . [and] the paucity of microscopic abnormalities was equally surprising.” The author concluded: “It is also remarkable how the observations in this case differ from the extensive, gross and microscopic changes which have been observed in the one proved case of ‘congenital’ encephalitis due to toxoplasma (Sabin AB, Toxoplasmic encephalitis in children, JAMA 1941;116:801–807). Other case reports have also noted the paucity of CNS findings in adult toxoplasmosis; however, one study reported widespread pathological findings in other organs, including the liver and spleen (Callahan WP, Russell WO, Smith MG, Human toxoplasmosis: a clinicopathologic study with presentation of five cases and review of the literature, Medicine 1946;25:343–397).
T. gondii is known to be highly neurotropic and to infect both neurons and astrocytes (Halonen SK, Lyman WD, Chiu FC, Growth and development of Toxoplasma gondii in human neurons and astrocytes, J Neuropath Exp Neurol 1996;55:1150–1156; Cruzet C, Robert F, Roisin MP et al., Neurons in primary culture are less efficiently infected by Toxoplasma gondii than glial cells, Parasitol Res 1998;84:25–30). In non-immunosuppressed individuals who are diagnosed with acute toxoplasmic encephalitis, the CSF shows moderately elevated protein, normal glucose levels, and T. gondii “is rarely isolated from the CSF.” Necrosis and an intense inflammatory reaction are seen on autopsy (Post MJD, Chan JC, Hensley GT, Toxoplasma encephalitis in Haitian adults with acquired immunodeficiency syndrome: a clinical-pathologic-CT correlation, Am J Roentgenol 1983;140:861–868). In immunosuppressed individuals, T. gondii may cause an acute necrotizing encephalitis that is most severe in the frontal and parietal lobes, basal ganglia, and thalamus (Shankar SK, Mahadevan A, Satishchandra P et al., Neuropathology of HIV/AIDS with an overview of the Indian scene, Indian J Med Res 2005;121:468–488; Dellacasa-Lindberg I, Hitziger N, Barragan A, Localized recrudescence of Toxoplasma infections in the central nervous system of immunocompromised mice assessed by in vivo bioluminescence imaging, Microbes Infect 2007;9:1291–1298).
Less information is available on the neuropathology of individuals chronically infected with T. gondii with bradyzoites. A study of 46 postmortem cases of AIDS patients with T. gondii infection reported “one case with intact tissue cysts in the parietal white matter as the only histopathologically identifiable lesion” (Strittmatter C, Lang W, Wiestler OD et al., The changing pattern of human immunodeficiency virus-associated cerebral toxoplasmosis: a study of 46 postmortem cases, Acta Neuropathol 1992;83:475–481).
- Neuropath studies of T. gondii in schizophrenia
One study has been carried out. Conejero-Goldberg studied the orbital frontal cortex of postmortem specimens from 14 individuals with schizophrenia, 11 with other psychiatric diagnoses, and 26 normal controls. The primers “were designed to amplify a conserved region in the parasitic genome and a fragment of the hsp/Bag1gene (a bradyzoite-expressed gene)” using a nested polymerase chain reaction. All specimens were negative (Conejero-Goldberg C, Torrey EF, Yolken RH, Herpesviruses and Toxoplasma gondii in orbital frontal cortex of psychiatric patients, Schizophr Res 2003;60:65–69).
In addition to neuropathological studies, it is also possible to identify the presence of T. gondii in brain tissue by inoculating the brain tissue into mice known to be uninfected and then looking for evidence of infection. A 1965 study that did this with brain autopsy tissue from 44 individuals known to have serological antibodies to T. gondii reported that the mice became antibody-positive in 4 of the 44 cases. In other cases, in addition to the 44, the mice became antibody-positive after being injected with muscle tissue (Remington JS, Cavanaugh AB, Isolation of the encysted form of Toxoplasma gondii from human skeletal muscle and brain, N Engl J Med 1965;273:1308–1310).
Current SMRI-funded research in this area
Sandra Holonen, Montana State University. Schizophrenia and Toxoplasma gondii brain pilot study.
VIII. Treatment Approaches to Toxoplasmosis and Schizophrenia
§ Background: Protozoa
Antipsychotic medications have been shown to have antiprotozoal activity. As early as 1891, it was reported that the phenothiazine dye methylene blue killed Plasmodium vivax, one causative agent of malaria (Guttman P, Ehrlich P, Über die wirkung des Methylenglau bei Malaria, Berl Klin Wochenschr 1891;39:953–956). In more recent years, in vitro studies have shown that phenothiazines such as chlorpromazine inhibit the growth of Tetrahymena pyriformis (Forrest IS, Quesada F, Deitchman GL, Unicellular organisms as model systems for the mode of action of phenothiazine and related drugs, Proc West Pharmacol Soc 1963;6:42–44); Paramecium spp. (Saitow F, Nakaoka Y, The photodynamic action of methylene blue on the ion channels of Paramecium causes cell damage, Photochem Photobiol 1997;65:902–907); Leishmania donovani (Pearson RD, Manian AA, Hall D et al., Antileishmanial activity of chlorpromazine, Antimicrob Agents Chemother 1984;25:571–574); Trypanosoma brucei and Trypanosoma cruzi (Benson TJ, McKie JH, Garforth J et al., Rationally designed selective inhibitors of trypanothione reductase. Phenothiazines and related tricyclics as lead structures, Biochem J 1992;286:9–11; Gutierrez-Correa J, Fairlamb AH, Stoppani AO, Trypanosoma cruzi trypanothione reductase is inactivated by peroxidase-generated phenothiazine cationic radicals, Free Radic Res 2001;34:363–378; Seebeck T, Gehr P, Trypanocidal action of neuroleptic phenothiazines in Trypanosoma brucei, Mol Biochem Parasitol 1983;9:197–208); Plasmodium falciparum (Kristiansen JE, Jepsen S, The susceptibility of Plasmodium falciparum in vitro to chlorpromazine and the stereo-isometric compounds cis(Z)- and trans(E)-clopenthixol, Acta Pathol Microbiol Immunol Scand B 1985;93:249–251); and Entamoeba histolytica (Ondarza RN, Hernandez E, Itrube A et al., Inhibitory and lytic effects of phenothiazine derivatives and related tricyclic neuroleptic compounds on Entamoeba histolytica HK9 and HM1 trophozoites, Biotechnol Appl Biochem 2000;32:61–67). In addition, an in vivo study reported that chlorpromazine ointment was effective in treating cutaneous leishmaniasis (Henriksen T-H, Lende S, Treatment of diffuse cutaneous leishmaniasis with chlorpromazine ointment (letter), Lancet 1983;i:26).
The first report of antipsychotic inhibition of Toxoplasma gondii was an in vitro study using the phenothiazine trifluoperazine (Stelazine), which was said to have “membrane-active detergent-like effects” on T. gondii (Pezzella N, Bouchot A, Bonhomme A et al., Involvement of calcium and calmodulin in Toxoplasma gondii tachyzoite invasion, Eur J Cell Biol 1997;74:92–101). An extensive in vitro study of eight antipsychotics and metabolites and four mood stabilizers compared their effectiveness in inhibiting T. gondii against the effectiveness of trimethroprim, a standard treatment for toxoplasmosis. Haloperidol was more effective than trimethoprim. Valproic acid and sodium valproate were equally effective to trimethoprim. Chlorpromazine, fluphenazine, risperidone, clozapine, quetiapine, and carbamazapine all showed some activity but less than trimethoprim. Lithium showed no inhibition of T. gondii (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;62:237–244).
§ Trials of drugs known to be effective against T. gondii on patients with schizophrenia
§ azithromycin (Zithromax) 600 mg: 56 outpatients with schizophrenia;
double-blind, placebo trial; 16 weeks; add-on to regular antipsychotic;
negative study (Dickerson et al., Sheppard Pratt Hospital, Baltimore).
§ trimethoprim 200 mg: 91 male outpatients with mostly chronic schizophrenia;
double-blind, placebo trial; 6 months; add-on to chlorpromazine or haloperidol.
Both groups improved markedly, perhaps reflecting being on a regular
antipsychotic with monitoring and follow-up. The trimethoprim group improved
more on the negative symptom subscale, but the difference did not achieve
statistical significance (Shibre et al., Butajira, Ethiopia, being submitted for publication).
§ trimethoprim 160 mg–sulfamethoxazole 800 mg (Bactrim DS): 80 inpatients
with chronic schizophrenia; open-label; 16 weeks; add-on to regular medication.
Bactrim group showed more improvement at 8 weeks but not at 16 weeks
(Desta et al., Addis Ababa, Ethiopia).
§ trimethoprim 480 mg–sufamethoxazole 2400 mg (Bactrim): 82 schizophrenia
and 61 bipolar patients; double-blind, placebo trial; 6 weeks; add-on to
flexible-dose risperidone 1–6 mg; Bactrim improved psychotic symptoms but
just short of statistical significance (p=0.059); patients on Bactrim needed
significantly lower doses of risperidone (Quiying et al., Wuhan, China).
§ pyrmethamine 75 mg–sufadiazine 2 g (Fansidar): 14 patients with acute schizophrenia; double-blind, placebo trial; 14 days; add-on to regular antipsychotic; both groups improved; numbers too small to do meaningful analysis (Hinze-Selch et al., Germany)
Current SMRI-funded research in this area
§ artemether 80 mg: 100 patients with schizophrenia; double-blind, placebo trial;
8 weeks; add-on to risperidone (Wang et al., Wuhan, China).
§ artemisinin 200 mg: 62 outpatients with schizophrenia; double-blind, placebo trial;
12 weeks; add-on to regular antipsychotic (Dickerson et al., Sheppard Pratt Hospital,
Baltimore).
§ trimethoprim 320 mg–sulfamethoxazole 1600 mg (Bactrim): 250 patients with first-episode schizophrenia; double-blind, placebo trial; 6 weeks; add-on to regular antipsychotics (Gallo et al., Lima, Peru). |
|
|