Toxoplasmosis-Schizophrenia Research Minimize


Toxoplasmosis–Schizophrenia Research

(last updated Feb 2014)

Welcome to the Toxoplasmosis–Schizophrenia Research section. This site is maintained by the Stanley Medical Research Institute (SMRI) and the Stanley Division of Developmental Neurovirology for researchers and others 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, MD, or Robert H. Yolken, MD.

Related sites:

ToxoDB: provides detailed information on the genome of Toxoplasma gondii 

Schizophrenia Research Forum: a useful online forum to keep updated on schizophrenia research

 

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 became infected with T. gondii  during their pregnancy, risked 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. Infection with T. gondii  in other adults and children was 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 more than $40 billion a year.

For additional information on schizophrenia, see Torrey EF, Surviving Schizophrenia, 6th edition (New York, HarperCollins, 2013). 

 

TOPICS OF INTEREST

I.       All about Cats

II.      Transmission of T. gondii 

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 to Toxoplasmosis and Schizophrenia

 

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” (Budiansky S. The Character of Cats. New York: Viking; 2002:6). 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! A feline history of the West. The American West. 1978;15:32-35,50).

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 they occasionally 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 worshipping a cat goddess (Bastet) became widespread. Cats were highly valued and often mummified when they died. DNA sequencing from an Egyptian mummy found T. gondii  DNA sequences in 2013 (Khairat R, Ball M, Chang CC, et al. First insights into the metagenome of Egyptian mummies using next-generation sequencing. J Appl Genet. 2013). 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; 1990:21).

  • 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 worshiping 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; 1988:156).

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; 1994:119).

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 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” (Méry F. The Life, History and Magic of the Cat. London: Paul Hamlyn; 1967:56, 59). Finally, as Pasteur’s work on 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.” “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 one 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 of cats

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.

In the United States, there was a 50% increase in owned cats reported between 1989 and 2006 (US Census Bureau. Surveys by the American Veterinary Medical Association, 1987 and 2006. In Statistical Abstract of the United States. U.S. Government Printing Office; 2010). In many American families, cats have close contact with their owners; one American study reported that 62% of cats slept with their adult owners and another 13% slept with children (Chomel BB, Sun B. Zoonoses in the bedroom. Emerg Infect Dis. 2011;17:167-172).

There has also been a marked increase in recent years in the keeping of cats as pets in developing countries as people become more affluent. For example, a study of T. gondii  oocysts in public parks was also recently carried out in Wuhan, China (Du F, Feng HL, Nie H, et al. Survey on the contamination of Toxoplasma gondii  oocysts in the soil of public parks of Wuhan, China. Vet Parasitol. 2012;184:141-146); under the regime of Mao Zedong, the keeping of pets was considered bourgeois and discouraged. Pet keeping only started to become prevalent after the death of Mao in 1976 and did not become common until recent years (Eckholm E. Dog’s life in China: Hiding from police dragnets. New York Times, 2001; Zhu S. Psychosis may be associated with Toxoplasmosis. Med Hypotheses. 2009;73:799-801). Yet, when 252 soil samples were taken from six public parks in Wuhan in 2009 and 2010, 58 samples (23%) contained T. gondii  oocysts. The soil samples were taken from areas frequented by cats. The wider prevalence of T. gondii  in modern China is also reflected in surveys of T. gondii  seropositivity in pregnant women. In seven studies between 1996 and 2004, the average seropositivity rate was found to be 4.5%, but in six studies completed since 2004 the average rate was 10.2% (Zhou P, Chen Z, Li HL, et al. Toxoplasma gondii  infection in humans in China. Parasit Vectors. 2011;4:165).

Counting cats is notoriously difficult. In the United States, it has been estimated that there are approximately 90 million pet cats, which are found in one-third of all households, and an additional 70 million or more feral cats, thus totaling at least 160 million (Dabritz HA, Conrad, PA. Cats and Toxoplasma: Implications for public health. Zoonoses Public Health. 2010;57:34-52). 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 (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. This brief two-to-three-week period is generally thought to be the only time during the life of that cat when it is infectious. There is some evidence, however, that some cats may later have a reactivation of their T. gondii  infection if they are later infected with other viruses, such as the feline immunodeficiency virus, or are stressed, and they may excrete oocysts and again become infectious at that time (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; 2004:58–124). 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). Insofar as these communities are representative of the United States population, the 81.7 million owned cats would produce 856,930 tons of outdoor cat feces each year. Assuming there are only 25 million feral cats, these would produce another 360 459 tons of cat feces, resulting in a total accumulation of 1,217,389 tons deposited annually in the environment of the United States (Torrey EF, Yolken RH. Toxoplasma oocysts as a public health problem. Trends Parasitol. 2013;29:380-4). A review of this estimate in the Los Angeles Times claimed that this weight of cat feces was the equivalent of 12 aircraft carriers (Morin M. Is your kitty’s poop a public health threat? Los Angeles Times, July 9, 2013).

The oocysts are remarkably stable, especially if they are deposited in shady, moist, and temperate conditions. In Texas, under outdoor shaded conditions with a mean air temperature of 19.5C, oocysts remained viable during a 13 month experiment (Yilmaz SM, Hopkins SH. Effects of different conditions on duration of infectivity of Toxoplasma gondii  oocysts. J Parasitol. 1972;58:938-9). In Kansas, oocysts were buried in loose soil and remained viable for 18 months (Frenkel JK, Ruiz A, Chinchilla M. Soil survival of Toxoplasma oocysts in Kansas and Costa Rica. Am J Trop Med Hyg. 1975;24:439-43). Oocysts maintained experimentally at 4C in seawater or freshwater remained viable for 24 and 54 months, respectively (Dubey JP. Toxoplasma gondii  oocyst survival under defined temperatures. J Parasitol. 1998;84:862-5, Lindsay DS, Dubey JP. Long-term survival of Toxoplasma gondii  sporulated oocysts in seawater. J Parasitol. 2009;95:1019-20). Oocysts also survived for over a year in vials of 2% sulfuric acid at 4C (Frenkel JK, Dubey JP. Toxoplasmosis and its prevention in cats and man. J Infect Dis. 1972;126:664-73). Since almost all of these studies were terminated while at least some of the oocysts were still viable, we do not yet know the outer limit of viability for T. gondii  oocysts deposited in various environmental conditions.

Given this large number of T. gondii  oocysts, what is the effect of this oocyst burden on a specific community? In the three California communities cited above, the T. gondii  annual oocyst burden was calculated by dividing the cat feces by the land area of residential housing. The communities differed by size and number of cats (Dabritz HA, Atwill ER, Gardner IA, Miller MA, Conrad PA. 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). Depending on estimations of oocyst production by the cats, the number of T. gondii  oocysts ranged from 9 to 434 per square foot (Dabritz HA, Miller MA, Atwill ER, et al. Detection of Toxoplasma gondii-like oocysts in cat feces and estimates of the environmental oocyst burden. J Am Vet Med Assoc. 2007;231:1676-84). A similar study was carried out in three communities in rural France, using comparable assumptions, and reported that the annual environmental oocyst burden varied from 3 to 335 oocysts per square foot (Afonso E, Thulliez P, Gilot-Fromont E. Local meteorological conditions, dynamics of seroconversion to Toxoplasma gondii  in cats (Felis catus) and oocyst burden in a rural environment. Epidemiol Infect. 2010;138:1105-13). In another French study, T. gondii  oocysts were identified in 8 of 62 soil samples collected from cat defecation sites on the grounds of an urban hospital (Afonso E, Lemoine M, Poulle ML, et al. Spatial distribution of soil contamination by Toxoplasma gondii  in relation to cat defecation behaviour in an urban area. Int J Parasitol. 2008;38:1017-23). In Brazil, T. gondii  oocysts were isolated from 10 soil samples taken from the playgrounds of 31 elementary schools; the authors suggested that these results indicated a wide distribution of T. gondii  oocysts around elementary schools in the region (dos Santos TR, Nunes CM, Luvizotto MC, et al. Detection of Toxoplasma gondii  oocysts in environmental samples from public schools. Vet Parasitol. 2010;171:53-7). In a village in Panama, it was estimated that the oocyst burden in soil near houses where cats are fed varied from 18 to 72 per square foot (Sousa OE, Saenz RE, Frenkel JK. Toxoplasmosis in Panama: a 10-year study. Am J Trop Med Hyg. 1988;38:315-322). In Poland, T. gondii  oocysts were isolated from 18 of 101 soil samples taken from places thought to be favored by cats for defecation: sandboxes, playgrounds, parks, gardens, and areas around rubbish pits (Lass A, Pietkiewicz H, Modzelewska E, Dumètre A, Szostakowska B, Myjak P. Detection of Toxoplasma gondii  oocysts in environmental soil samples using molecular methods. Eur J Clin Microbiol Infect Dis. 2009;28:599-605).

 

II.  Transmission of T. gondii

T. gondii  can be acquired by humans in several different ways. It may be transmitted as a tissue cyst, usually by eating undercooked meat from an infected animal, or as an oocyst.

  • Ingestion of Tissue cysts

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)..

  • Ingestion or Inhalation of Oocysts

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. One study of young children reported that children who are under three years of age put their hands or other objects in their mouths every 2 to 3 minutes (Black RE, Merson MH, Huq I, Alim AR, Yunus M. Incidence and severity of rotavirus and Escherichia coli diarrhoea in rural Bangladesh. Implications for vaccine development. Lancet. 1981;1:141-3). Another study, which included 64 children between one and four years old, carried out in a Massachusetts day care center reported that the children ingested a median of 40 mg of soil per day; furthermore, one child consumed 5 to 8 g of soil per day on average (Calabrese EJ, Barnes R, Stanek EJ 3rd, et al. How much soil do young children ingest: an epidemiologic study. Regul Toxicol Pharmacol. 1989;10:123-37). 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 cysts in 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 of oocysts from cats especially via water, and contaminated fruits and vegetables, is thought to be more important (Boyer K, Hill D, Mui, E, et al. Unrecognized ingestion of Toxoplasma gondii  oocysts leads to congenital toxoplasmosis and causes epidemics in North America. Clin Infect Dis. 2011;53:1081-9). Recent studies have reported that the majority of congenital infections (Boyer K, Hill D, Mui E, et al. Unrecognized ingestion of Toxoplasma gondii  oocysts leads to congenital toxoplasmosis and causes epidemics in North America. Clin Infect Dis. 2011;53:1081-9) and postnatal acute infections (Hill D, Coss C, Dubey JP, et al. Identification of a sporozoite-specific antigen from Toxoplasma gondii. J Parasitol. 2011;97:328-37) in the United States are from oocysts.

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).

  • Vertical Transmission from Infected Mother to Offspring

In humans, it is well known that if a previously uninfected woman is infected with T. gondii  while pregnant, the T. gondii  may cross the placenta and cause brain damage (e.g., cysts, seizures, mental retardation) in the offspring. This is why women are cautioned to not change cat litter while they are pregnant.

In female mice, it is known that a mouse which has been infected with T. gondii, even before becoming pregnant, may pass along the T. gondii  to their offspring. This may occur in subsequent litters as well so that the infected mouse mother may infect many offspring. (Owen MR, Trees AJ. Vertical transmission of Toxoplasma gondii  from chronically infected house (Mus musculus) and field (Apodemus sylvaticus) mice determined by polymerase chain reaction. Parasitology. 1998;116:299-304). More surprising is the vertical transmission of T. gondii  from an infected mouse to its offspring, then from this offspring to its offspring, and on for up to five generations (Beverly JKA. Congenital transmission of Toxoplasmosis through successive generations of mice. Nature. 1959;183:1348-1349). This would give the appearance of being a genetic disease with maternal inheritance, but in reality, would simply be the vertical transmission of an infectious agent.

  • Sexual Transmission of T. gondii

A study in dogs demonstrated that T. gondii  can be transmitted sexually in that species. Male dogs were infected by T. gondii ; it was then found in their semen. The infected semen was then used to artificially inseminate four uninfected female dogs. Seven days after insemination, all four dogs had antibodies to T. gondii. Two of the pregnant dogs had miscarriages; the other two delivered four puppies, none of whom lived longer than three weeks and all of which had cysts containing T. gondii  in their brains (Arantes TP, Lopes WD, Ferreira RM, et al. Toxoplasma gondii : evidence for the transmission by semen in dogs. Exp Parasitol. 2009;123:190–194). Another study demonstrated that T. gondii  can be sexually transmitted in rats; 43 of 69 rat pup offspring, following sexual transmission, were found to be infected (Dass SAH, Vasudevan A, Dutta D, et al. Protozoan parasite Toxoplasma gondii  manipulate mate choice in rats by enhancing attractiveness of males. PLoS One. 2011;11:e27229. doi:10.1371/journal.pone.0027229). Most recently, it was demonstrated that T. gondii  can be sexually transmitted in sheep; infected males were able to infect previously-uninfected females and the infection was then transmitted vertically to their lambs (Lopes WDZ, Rodriguez JD, Souza FA, et al. Sexual transmission of Toxoplasma gondii  in sheep. Vet Parasitol. 2013;195:47-56).

There is also evidence that T. gondii  can be sexually transmitted in humans. How often this actually happens and its clinical importance are unknown. A study in Germany examined semen collected from 125 men who were being examined for possible infertility. Among the 125, 3 men had evidence of T. gondii  in their semen. Two of the men also had blood antibodies to T. gondii, but the third did not. One man had urethritis and another had gonorrhea (Disko R. Braveny I, Vogel P. Untersuchungen zum Vorkommen von Toxoplasma gondii  im menschlichen Ejakulat. [Studies on the occurrence of Toxoplasma gondii  in the human ejaculate]. Z. Tropenmed. Parasitol. 1971;22:391-6).

An American study examined the testes of 10 men who had died from AIDS and T. gondii  opportunistic infection. In 6 of the 10 cases bradyzoite-filled cysts were identified in the testes. In 4 of these 6 cases, the only other organ in which T. gondii  was found was the brain (De Paepe M, Guerrieri C, Waxman M. Opportunistic infections of the testis in the Acquired Immunodeficiency Syndrome. Mt Sinai J Med. 1990;57:25-29).

  • Do people with close cat contact have a greater chance of being infected with T. gondii?

As noted previously, T. gondii  can be transmitted from cats to humans in many different ways. Being bitten by a cat, however, apparently does not cause the transmission of T. gondii  (Westling K, Jorup-Ronstrom C, Evengard B. Toxoplasmosis not transmitted by cat bite, but high prevalence of antibodies to Toxoplasma gondii  in patients bitten by their own cat. Scand J Infect Dis. 2010;42:687–690). Some of the means of transmission 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; 2001:85–91). 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). An American study reported that living in a household with one or two kittens was not a significant risk factor for becoming infected with T. gondii, but living in a household with three or more kittens was a highly significant risk factor (OR 35.4) (Jones JL, Dargelas V, Roberts J, et al. Risk factors for Toxoplasma gondii  infection in the United States. Clin Infect Dis. 2009;49:878–884).

  • Do children with close cat contact have a greater chance of developing schizophrenia?

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.

A few of the T. gondii  antibody studies (see section V) have also collected information on cat exposure. For example, a Turkish study of 73 patients with first-episode schizophrenia and 40 controls reported that 15/73 (28%) of the patients had a cat in their house compared to 1/40 (3%) of the controls (p=0.006) (Tanyuksel M, Uzun O, Araz E, et al. Possible role of toxoplasmosis in patients with first-episode schizophrenia. Turk J Med Sci. 2010;40:399–404).

 

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 more than one hundred candidate predisposing genes have been identified. Many of the candidate genes predisposing to schizophrenia have been shown to be activated by Toxoplasma infection in cell cultures and in experimental animals. (For a detailed analysis of the effect of T. gondii  on genes which have been linked to schizophrenia see Carter CJ. Toxoplasmosis and polygenic disease susceptibility genes: Extensive Toxoplasma gondii  host/pathogen interactome enrichment in nine psychiatric or neurological disorders. J Pathogens. 2013;2013:965046). Of particular importance was the activation of microRNAs such as mi132 and mi137 since these microRNAs have been implicated in schizophrenia by genetic studies.

Toxoplasmosis has also been observed to be familial but not necessarily for genetic reasons. A familial pattern to the disease has been observed, 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). In one study of family transmission, it was found that in half of the families in which one person becomes infected with acute toxoplasmosis, as second member of the family also becomes infected (Contopoulos-loannidis DG, Maldonado Y, Montoya JG. Acute Toxoplasma gondii  infection among family members in the United States. Emerg Infect Dis. 2013;19:1981-1984. 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; Blackwell JM, Roberts CW, Alexander J. Influence of genes within the MHC on mortality and brain cyst development in mice infected with Toxoplasma gondii : kinetics of immune regulation in BALB H-2 congenic mice. Parasite Immunol. 1993;15:317–324). 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; Owen MR and Trees AJ. Vertical transmission of Toxoplasma gondii  from chronically infected house [Mus musculus] and field [Apodemus sylvaticus] mice determined by polymerase chain reaction. Parasitology. 1998;116:299–304).

  • 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). The peak age of primary infections with T. gondii  was also shown in a Dutch study to be “adolescence and early adult life,” with a peak at ages 17 to 20 (van der Veen J, Polak MF. Prevalence of Toxoplasma antibodies according to age with comments on the risk of prenatal infection. J Hyg (Camb). 1980;85:165–174).

Figure 1. Comparison of age of onset of schizophrenia and toxoplasmosis

      Age of onset of schizophrenia as determined by first admission

     Figure 1 Comparison of age of onset of schizophrenia and toxoplasmosis.JPG

 

      Age of onset of adult toxoplasmosis as determined by lymphadenopathy

     Figure 1 Age of onset of adult by lymphadenopathy.JPG

 

  • 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 and 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.

Seven 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 T, Novak-Antolic Z. 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. 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). 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). Finally, a study from Serbia reported that among 391 cases of recent lymphadenopathy caused by T. gondii, the acute infections occurred more often between October and March (p=0.05) (Bobic B, Klun I, Nikolic A, et al. Seasonal variations in human Toxoplasma infection in Serbia. Vector-Borne Zoonotic Dis. 2010;10:465–469).

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 & 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 and 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 unclear or 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; 2001:58–124).

  • 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 (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). 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. Epidemiol 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). Much subsequent work has been carried out in rodents; see, for example, Kannan G, Pletnikov MV. Toxoplasma gondii  and cognitive deficits in schizophrenia: An animal model perspective. Schizophr Bull. 2012;38:1155-61).

  • Behavioral manipulation by T. gondii  in rodents

(see also section VI. Neurotransmitters and T. gondii)

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 behavior. Microbes Infect. 2001;3:1037–1045). Webster and Glenn McConkey have also speculated about specific mechanisms that may explain the parasite manipulation (Webster JP, McConkey GA. Toxoplasma gondii -altered behaviour: clues as to mechanism of action. Folia Parasitol. 2010;57:95–104). A recent summary of this work is Webster JP, Kaushik M, Bristow GC, McConkey GA. Toxoplasma gondii  infection, from predation to schizophrenia: can animal behavior help us understand human behavior? J Exp Biol. 2013;216:99-112 and Kaushik M, Lamberton PHL, Webster JP. The role of parasites and pathogens in influencing generalized anxiety and predation-related fear in the mammalian central nervous system. Horm Behav. 2012;62:191-201.

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). They also speculated regarding possible pathophysiological mechanisms (Vyas A, Sapolsky R. Manipulation of host behaviour by Toxoplasma gondii : what is the minimum a proposed proximate mechanism should explain? Folia Parasitol. 2010;57:88–94) and showed that one of the mechanisms used by T.gondii  is to activate sexual arousal pathways of the rats (House PK, Vyas A, Sapolsky R. Predator cat odors activate sexual arousal pathways in brains of Toxoplasma gondii  infected rats. PLoS One. 2011;6:e23277).

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;12:528-537). It has also been shown that the effects of T. gondii  in rodents is sex specific as assessed by gene expression. A study of this specificity concluded that “the sex of the host plays a major role in determining variable brain and behavior changes following Toxoplasma  infection” (Xiao J, Kannan G, Jones-Brando L, et al. Sex-specific changes in gene expression and behavior induced by chronic Toxoplasma infection in mice. Neuroscience. 2012;206:39-48).

Another interesting example of the effects of T. gondii  on animal behavior is the sea otters who live on the coast of California. Many have become infected with T. gondii, presumably because of rainwater runoff from cat-infested areas carrying the oocysts into the ocean. A 2004 study reported that sea otters with toxoplasmosis were 3.7 times more likely to be attacked by sharks than others who were not infected (Miller MA, Grigg ME, Kreuder C, et al. An unusual genotype of Toxoplasma gondii  is common in California sea otters (Enhydra lutris nereis) and is a cause of mortality. Int J Parasitol. 2004;34:275-84.

  • Effects of T. gondii  on personality traits of humans

Jaroslav Flegr () 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. Thus, sex differences of the effect of T. gondii  in humans have been shown, just as they have been in rodents. Flegr has summarized these findings (Flegr J. Effects of Toxoplasma on human behavior. Schizophr Bull. 2007;33:757–760; Flegr J. Influence of latent toxoplasmosis on the phenotype of intermediate hosts. Folia Parasitol. 2010;57:81–87). An article describing Flegr’s research was also published in the Atlantic magazine (McAuliff K. How your cat is making you crazy. March 2012).

  • Effects of T. gondii  on cognition in humans

The effects of T. gondii  on cognitive measures in humans has been studied by our laboratory (Yolken RH, Dickerson FB, Torrey EF. Toxoplasma and schizophrenia. Parasite Immunol. 2009;31:706–715). We measured Toxoplasma IgG antibodies and cognitive functioning in 291 individuals between the ages of 19 and 60 who did not have a history of a psychiatric disorder. As depicted in Figure 2, we found that individuals with serological evidence of Toxoplasma infection had significantly worse performance in measures of delayed memory (p<0.002) and immediate memory (p<0.05) and trends toward worse performance in other domains. On the other hand, Toxoplasma serostatus was not associated with demographic variables that might affect the results of cognitive testing such as age, gender, race, or level of education. Additional studies have been performed to further define the association between exposure to Toxoplasma and cognitive impairment in other populations.

Figure 2. Cognitive functioning in individuals with and without serological evidence of Toxoplasma infection.

Fig 2 cognitive update.jpg

A total of 291 individuals between the ages of 19 and 60 without a history of a psychiatric disease underwent cognitive testing and had their serum IgG antibodies measured to Toxoplasma gondii. A total of 39 (13.4%) of the individuals had serological evidence of Toxoplasma infection as defined by antibody levels > 10 international units. The bars indicate the mean performance on cognitive tasks with the results standardized so that the mean value in the Toxoplasma seronegative group is equal to one. The error bars indicate the 95% confidence intervals of the mean values. The tests performed are as follows: Del Mem, RBANS Delayed Memory; Imm Mem, RBANS Immediate Memory; Vis Con, RBANS Visuospatial/Constructional; Attent, RBANS Attention; Lang., RBANS Language; RBANS Tot, RBANS Total Score; WCS Per Err, Wisconsin Card Sorting Task perseverative errors; WCS Comp, Wisconsin Card Sorting Task categories completed; Let Num Sc, Letter Number test scaled score; Trial Sc, Trail Making Test A scaled score. The indicated p values are computed from linear regression models that include age, gender, race, and level of education.

A study in Brazil carried out in 100 schoolchildren reported that the children infected with T. gondii  did more poorly on some academic tests, especially in mathematics (Ferreira EC, Marchioro AA, Guedes TA, et al. Association between seropositivity for Toxoplasma gondii, scholastic development of children and risk factors for T. gondii  infection. Trans R Soc Trop Med Hyg. 2013;107:390-6). Other studies carried out in healthy elderly individuals have reported that infection with T. gondii  is associated with greater memory impairment (Gajewski PD, Falkenstein M, Hengstler JG, Golka K. Toxoplasma gondii  impairs memory in infected seniors. Brain Behav Immun. 2014;36:193-9) and deficits in goal-directed behavior (Beste C, Getzmann S, Gajewski PD, Golka K, Falkenstein M. Latent Toxoplasma gondii  infection leads to deficits in goal-directed behavior in healthy elderly. Neurobiol Aging. 2014;35:1037-44).

  • Effects of T. gondii  on the behavior of humans

Flegr et al. also compared his infected and uninfected human subjects 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). Pearce et al. also demonstrated psychomotor slowing in healthy humans, as well as in those with schizophrenia, who were infected with T. gondii  compared with those not infected (Pearce BD, Hubbard S, Rivera HN, et al. Toxoplasma gondii  exposure affects neural processing speed as measured by acoustic startle latency in schizophrenia and controls. Schizophr Res. 2013;150:258-61.

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). This research group subsequently replicated this finding in another driver cohort in the Czech Republic (Flegr J, Klose J, Novotna M, et al. Increased incidence of traffic accidents in Toxoplasma-infected military drivers and protective effect RhD molecule revealed by a large-scale prospective cohort study. BMC Infect Dis. 2009;9:e72).

In Turkey, there have been two replications showing an association between individuals involved in traffic accidents and infection with T. gondii. In a case-control study, Yereli et al. 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). This study has been replicated by another study in Turkey (Kocazeybek B, Oner YA, Turksoy R, et al. Higher prevalence of toxoplasmosis in victims of traffic accidents suggest increased risk of traffic accident in Toxoplasma-infected inhabitants of Istanbul and its suburbs. Forensic Sci Int. 2009;187:103–108). In view of this association between traffic accidents and T. gondii, researchers in Mexico assessed the T. gondii  antibody status in 133 individuals involved in work-related industrial accidents and 266 controls. Overall there was no association except among workers who also had low socioeconomic status (Alvarado-Esquivel C, Torres-Castorena A, Liesenfeld O, et al. High seroprevalence of Toxoplasma gondii  infection in a subset of Mexican patients with work accidents and low socioeconomic status. Parasites & Vectors. 2012;5:13).

  • 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. Rima McLeod, who has followed large numbers of such children over many years, reported that among the congenitally-infected cases “there have been only rare persons with these neuropsychiatric or other disease” (McLeod R, VanTubbergen C, Montoya JG, et al. Human toxoplasmosis infection. In LM Weiss and K Kim, eds., Toxoplasma gondii. Amsterdam:Elsevier;2013:109). 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; 2009:217–228). 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). A recent study of 156 suicide attempters and 127 controls in Mexico reported similar results. There was no statistical difference in seropositivity but the titers of the T. gondii  antibody was significantly higher (p=0.04) in the suicide attempters (Alvarado-Esquivel C, Sánchez-Anguiano LF, Arnaud-Gil CA, et al. Toxoplasma gondii  infection and suicide attempts: A case-control study in psychiatric outpatients. J Nerv Ment Dis. 2013;201:948-52). The association between suicide attempts and higher titre to T. gondii  antibodies was 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;199:15-17). A third study reported an association between suicide attempts and T. gondii  seropositivity in patients with schizophrenia, but the association was only significant in younger patients (Okusaga O, Langenberg P, Sleemi A, et al. Toxoplasma gondii  antibody titers and history of suicide attempts in patients with schizophrenia. Schizophr Res. 2011;133:150-155). In 2012 a Danish study reported that women who were infected with T.gondii  were significantly more likely to be suicidal and twice as likely to successfully commit suicide, compared to women not infected (Pedersen MG, Mortensen PB, Norgaard-Pedersen B, Postolache TT. Toxoplasma gondii  infection and self-directed violence in mothers. Arch Gen Psychiatry. 2012;doi:10.1001/archgenpsychiatry.2012.668) and in Sweden, a study of 54 adult suicide attempters reported increased seropositivity of T. gondii  (OR 7.12, p=0.08) compared to controls (Zhang Y, Träskman-Bendz L, Janelidze S, et al. Toxoplasma gondii  immunoglobulin G antibodies and nonfatal suicidal self-directed violence. J Clin Psychiatry. 2012;73:1069-76). Finally, a study of national suicide rates in 17 European nations reported a significant association between the prevalence of T. gondii  and the suicide rate (Lester D. Predicting European suicide rates with physiological indices. Psychol Rep. 2010;107:713-4).

Three other studies are of interests regarding the effect of T. gondii  on behavior and psychiatric symptoms. Holub and his colleagues in Prague divided individuals with schizophrenia into those with antibodies to T. gondii  (n=57) and those without such antibodies (n=194), then retrospectively assessed their clinical histories. The patients with antibodies were found to have had an earlier onset of their illness for men, but not women; to have more severe symptoms; and to have been hospitalized for longer (Holub D, Flegr J, Dragomirecká E, et al. Differences in onset of disease and severity of psychopathology between toxoplasmosis-related and toxoplasmosis-unrelated schizophrenia. Acta Psychiatr Scand. 2013;127:227-38).

Another study of interest was the effect of seropositivity to T. gondii  on the mortality rate of individuals with schizophrenia. In an earlier study, Dickerson et al. reported that antibodies for T. gondii  were associated with an increased mortality (Dickerson F, Boronow J, Stallings C, Origoni A, Yolken R. Toxoplasma gondii  in individuals with schizophrenia: Association with clinical and demographic factors and with mortality. Schizophr Bull. 2007;33:737-40). However, a later study reported that this relationship was no longer statistically significant when it was corrected for age and gender (Dickerson F, Stallings C, Origoni A, Schroeder J, Khushalani S, Yolken R. Mortality in Schizophrenia: Clinical and Serological Predictors. Schizophr Bull. 2013 Aug 13). Finally, a demographic study reported a correlation between the prevalence of T. gondii  and the national homicide rate in 20 European nations for the year 2000 (Lester D. Toxoplasma gondii  and homicide. Psychol Rep. 2012;111:196-7).

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.

  • The effects of different strains of T. gondii

Although at least 15 distinct strains of T. gondii  are known, most isolates of T. gondii  in Europe and North America belong to one of three strains: I, II, or III. Despite having more than 98 percent genetic identity, the effects of the three strains are quite different in rodents and are assumed to be so in humans as well. In mice, for example, the three strains produce significantly different gene expression (Hill RD, Gouffon JS, Saxton AM, Su C. Differential gene expression in mice infected with distinct Toxoplasma strains. Infect Immun. 2012;80(3):968-74). Studies of the three strains on gene expression in human neuroepithelial cells also show markedly different effects on gene expression, with type I exhibiting the highest level of gene expression (Xiao J, Jones-Brando L, Talbot CC Jr, et al. Differential effects of three canonical Toxoplasma strains on gene expression in human neuroepithelial cells. Infect Immun. 2011;79:1363–1373). It has also been shown that different strains of T. gondii  produce different effects on mouse behavior (Kannan G, Moldovan K, Xiao J-C, et al. Toxoplasma gondii  strain-dependent effects on mouse behavior. Folia Parasitol. 2010;57:151–155). Similarly, it is known that type I T. gondii  is much more lethal in mice than type II or type III, but it was not known whether or not this also applies to human infections. A 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). Another study from our laboratory showed that the different strains of T. gondii  had very different effects on neurotrasmitters (Xiao J, Li Y, Jones-Brando L, Yolken RH. Abnormalities of neurotransmitter and neuropeptide systems in human neuroepithelioma cells infected by three Toxoplasma strains. J Neural Transm. 2013;120:1631-9). In a related study, in human congenital T. gondii  infections, different strains of T. gondii  were found to produce differences in the incidence of premature births and eye disease (McLeod R, Boyer KM, Lee D, et al. Prematurity and severity are associated with Toxoplasma gondii  alleles (NCCCTS, 1981-2009). Clin Infect Dis. 2012;54:1595-605).

  • The effects of the timing of the initial T. gondii  infection

In mice it has been shown that the timing of the initial T. gondii  infection is an important determinant of outcome. For example, the outcome in mice infected at 4 weeks of age is very different from mice infected at 9 weeks of age. Additional research on this problem is in progress by Dr. Misha Pletnikov and his colleagues at John Hopkins University Medical Center.

 

 V.  Studies of T. gondii  Antibodies in Schizophrenia

  • Studies of antibodies in individuals who have schizophrenia

Antibody studies provide among the strongest evidence linking T. gondii   to schizophrenia. This is in spite of the fact that the standard assays currently in use to measure T. gondii  antibodies are far from perfect. Studies in our laboratory have suggested that the standard assays may miss many Toxoplasma-infected cases i.e., that many cases that are reported as negative are really positive if a more sensitive assay was available.

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 70 additional 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).

A 2012 updated meta-analysis of 38 such studies included 6,067 individuals with schizophrenia and 8,715 controls. The meta-analysis also reported an odds ratio of OR 2.71 (1.93–3.80) (Torrey EF, Bartko JJ, Yolken RH. Toxoplasma gondii : meta-analysis and assessment as a risk factor for schizophrenia. Schizophr Bull. 2012;38:642-647). These studies were done in 14 different countries; thus, the finding of increased antibodies against T. gondii  in individuals with schizophrenia has been remarkably consistent geographically and over half a century.

There is some clear evidence from these antibody studies that the increase in antibodies is not secondary to antipsychotic medication. The study by Leweke et al. in Germany assessed antibodies to T. gondii  in 36 individuals with schizophrenia who had never been treated, 10 who had had past treatment, and 39 receiving current treatment. The level of both serum and CSF antibodies to T. gondii  was highest in the never-treated patients, intermediate in those treated in the past, and lowest in those receiving current treatment (Leweke FM, Gerth CW, Koethe D, et al. Antibodies to infectious agents in individuals with recent onset schizophrenia. Eur Arch Psychiatry Clin Neurosci. 2004;254:4–8).

  • 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). An attempt was made to replicate this finding, using the same methodology, in a larger military cohort of 855 individuals with schizophrenia and 1,165 controls. The results failed to replicate the original finding (hazard ratio – 1.06, p=0.27) (Li Y, Weber NS, Fisher JA, et al. Association between antibodies to multiple infectious and food antigens and new onset schizophrenia among US military personnel. Schizophr Res. 2013;151:36-42).

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). However, a study of a larger group of Dutch adolescents who were assessed for “psychic experiences” reported no correlation between antibodies to T. gondii  and self-reports of “psychic experiences” (Wang H, Yolken RH, Hoekstra PJ, et al. Antibodies to infectious agents and the positive symptom dimension of subclinical psychosis: the TRAILS study. Schizophr Res. 2011;129:47–51).

Another study of antibodies in individuals prior to the onset of schizophrenia was carried out in Denmark using their national case register. Among 45,609 women who gave birth between 1992 and 1995 (at which time T. gondii  antibodies were assessed), 80 developed schizophrenia during the following 13–16 years, indicating a relative risk of 1.68 (0.77–3.46). “When the mothers were classified according to IgG level, only those with the highest IgG levels had a significantly higher risk of schizophrenia spectrum disorder” (Pedersen MG, Stevens H, Pedersen CB, et al. Toxoplasma infection and later development of schizophrenia in mothers. Am J Psychiatry. 2011;168:814-821).

A study in Wuhan, China, assessed antibodies to T. gondii  in 7,126 students entering Wuhan University for their first year. At the time of entering the university, 707 (9.9%) had IgG and 113 (1.6%) had IgM antibodies to T. gondii. The students were then followed for the next four years and all those who developed a psychotic disorder were noted. At the end of that time, 84 students (1.2%) had developed a psychotic disorder. Among those with psychosis, 18 (21.4%) had IgG antibodies and 9 (10.7%) had IgM antibodies to T. gondii  at the time they entered the university. Regarding T. gondii  as a risk factor for psychosis, 18 of the 707 (2.6%) students with IgG antibodies developed psychosis compared to 66 of the 6,419 (1.0%) students without IgG antibodies. Similarly, 9 of the 113 (8.0%) students with IgM antibodies developed psychosis compared to 104 of the 7,013 (1.5%) students without IgM antibodies (unpublished study).

  • 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).

In Sweden, Blomstrom et al. examined sera (filter paper samples) collected at birth in 1975-1985 on 198 individuals who were later diagnosed with schizophrenia and 524 matched controls. Levels of IgG antibodies to T. gondii  at birth were associated with the subsequent diagnosis of schizophrenia (OR=2.1, 95%CI 1.0-4.5) (Blomström A, Karlsson H, Wicks S, Yang S, Yolken RH, Dalman C. Maternal antibodies to infectious agents and risk for non-affective psychoses in the offspring--a matched case-control study. Schizophr Res. 2012;140:25-30).

  • 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).

  • Are increased antibodies to T. gondii  found in other psychiatric and/or neurological conditions?

It appears that increased antibodies to T. gondii  are not specific to schizophrenia. A study of 199 patients with bipolar disorder reported an increased prevalence compared to controls (Fekadu A, Shibre T, Cleare AJ. Toxoplasmosis as a cause for behaviour disorders—overview of evidence and mechanisms. Folia Parasitol. 2010;57:105–113). This finding was subsequently replicated in a smaller American sample (n=41) (Pearce BD, Kruszon-Moran D, Jones JL. The relationship between Toxoplasma gondii  infection and mood disorders in the third National Health and Nutrition survey. Biol Psychiatry. 2012;72:290-295). It was also replicated in a French sample of 110 bipolar disorder patients and 106 healthy controls (OR=2.2, p=0.028) (Hamdani N, Daban-Huard C, Lajnef M, et al. Relationship between Toxoplasma gondii  infection and bipolar disorder in a French sample. J Affect Disord. 2013;148:444-8). Yet another study from Brazil reported a significant increase in T. gondii  seropositivity in a small sample of patients with mood disorder (n=28, including 24 bipolar and 14 major depression) compared to healthy controls (n=95) (Nascimento FS, de Rosalmeida Dantas C, Netto MP, et al. Prevalence of antibodies to Toxoplasma gondii  in patients with schizophrenia and mood disorders. Schizophr Res. 2012;142:244-5).

A study of 42 patients with obsessive-compulsive disorder also reported an increased prevalence of antibodies to T. gondii  compared to controls (Miman O, Mutlu EA, Ozcan O, et al. Is there any role of Toxoplasma gondii  in the etiology of obsessive-compulsive disorder? Psychiatry Res. 2010;177:263–265). Similarly, a study of a large community cohort in Detroit reported that T. gondii  seropositivity was associated with a diagnosis of general anxiety disorder but not with PTSD or depression (Markovitz et al, submitted). Another  study of 414 pregnant women reported that the 44 women with antibodies to T. gondii  were more likely to be depressed and anxious (Groër MW, Yolken RH, Beckstead JW, et al. Prenatal depression and anxiety in Toxoplasma gondii  positive women. Am J Obstet Gynecol. 2011;204:433.e1-7).

One study of patients with Parkinson’s disease reported an increase in T. gondii  antibodies (Miman O, Kusbeci OY, Aktepe OC, et al. The probable relation between Toxoplasma gondii  and Parkinson’s disease. Neurosci Lett. 2010;475:129–131), but another study did not (Celik T, Kamisli O, Babur C, et al. Is there a relationship between Toxoplasma gondii  infection and idiopathic Parkinson’s disease? Scand J Infect Dis. 2010;42:604–608). Still other neurological studies have linked T. gondii  antibodies to migraine (Koseoglu E, Yazar S, Koc I. Is Toxoplasma gondii  a causal agent in migraine? Am J Med Sci. 2009;338:120–122) and possibly to cryptogenic epilepsy (Stommel EW, Seguin R, Thadani VM, et al. Cryptogenic epilepsy: an infectious etiology? Epilepsia. 2011;42:436–438). A small study of Alzheimer’s disease reported a significantly higher seropositivity for T. gondii  among patients than controls (Kusbeci OY, Miman O, Yaman M, Aktepe OC, Yazar S. Could Toxoplasma gondii  have any role in Alzheimer disease? Alzheimer Dis Assoc Disord. 2011;25:1-3). Finally, studies of brain cancers have suggested an association between the prevalence rate of such cancers and prevalence of T. gondii  (Vittecoq M, Elguero E, Lafferty KD, et al. Brain cancer mortality rates increase with Toxoplasma gondii  seroprevalence in France. Infect Genet Evol. 2012;12:496-8; Ryan P, Hurley SF, Johnson AM, et al. Tumours of the brain and presence of antibodies to Toxoplasma gondii. Int J Epidemiol. 1993;22:412-9).  

  • Are increased antibodies to T. gondii  found in other non-psychiatric, non-neurological diseases?

An increased prevalence of antibodies to T. gondii  has been reported in several other conditions. One study, for example, reported that “individuals with positive T. gondii  serology had twice the odds of being obese compared to seronegative individuals (p=0.01) (Reeves GM, Mazaheri S, Snitker S, et al. A positive association between T. gondii  seropositivity and obesity. Front Public Health. 2013;1:73).

Perhaps the most interesting association of T. gondii  with other diseases is with rheumatoid arthritis. Four studies have reported an increased prevalence of T. gondii  antibodies in individuals with this disease (Tomairek HA, Saeid MS, Morsy TA, Michael SA. Toxoplasma gondii  as a cause of rheumatoid arthritis. J Egypt Soc Parasitol. 1982;12:17-23; Mousa MA, Soliman HE, el Shafie MS, Abdel-Baky MS, Aly MM. Toxoplasma seropositivity in patients with rheumatoid arthritis. J Egypt Soc Parasitol. 1988;18:345-51; Shapira Y, Agmon-Levin N, Selmi C, et al. Prevalence of anti-toxoplasma antibodies in patients with autoimmune diseases.J Autoimmun. 2012;39:112-6; Fischer S, Agmon-Levin N, Shapira Y, et al. Toxoplasma gondii : bystander or cofactor in rheumatoid arthritis. Immunol Res. 2013;56:287-92). Another study reported that individuals with rheumatoid arthristis compared to controls have had more exposure to cats (Gottlieb NL, Ditchek N, Poiley J, Kiem IM. Pets and rheumatoid arthritis. An epidemiologic survey. Arthritis Rheum. 1974;17:229-34). This association is especially interesting because rheumatoid arthritis and schizophrenia share many epidemiological features and it has been noted in many studies that the two diseases are mutually exclusive, i.e., once you get either rheumatoid arthritis or schizophrenia, you almost never get the other (Torrey EF, Yolken RH. The schizophrenia-rheumatoid arthritis connection: infectious, immune, or both? Brain Behav Immun. 2001;15:401-10). This suggests that T. gondii  or another pathogen may cause both diseases with the clinical outcome differing because of genetic predisposition, timing of the initial infection, strain difference, or other.

  • 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. Epidemiologic implications of limited-duration seropositivity after Toxoplasma infection. Am J Epidemiol. 1990;132:169–180). There are at least two other studies of adult toxoplasmosis reporting conversions from T. gondii  seropositivity to seronegativity (van der Veen J, Polak MF. Prevalence of Toxoplasma antibodies according to age with comments on the risk of prenatal infection. J Hyg (Camb). 1980;85:165–174; Konishi E. Annual change in immunoglobulin G and M antibody levels to Toxoplasma gondii  in human sera. Microbiol Immunol. 1989;33:403–411) and one study showing a similar change in cases of congenital toxoplasmosis (Koppe JC, Kloosterman GJ. Congenital toxoplasmosis: long-term follow-up. Paediatrie und Paedologie. 1982;17:171–179). Serial antibody studies from our own laboratory also have recorded numerous individuals whose T. gondii  antibody status has switched from positive to negative over time.

 

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, copyright 1985, 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. McConkey et al. subsequently confirmed that T. gondii  does actually make dopamine and showed “a direct correlation between the number of infected cells and the quantity of dopamine released (Prandovszky E, Gaskell E, Martin H, et al. The neurotropic parasite Toxoplasma gondii  increases dopamine metabolism. PLoS One. 2011;6:e23866). 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).

Additional studies on the effect of T. gondii  on neurotransmitters being carried out in cell cultures in our laboratory have shown a differential effect of different strains on neurotransmitter-related gene expression (Xiao J, Li Y, Jones-Brando L, Yolken RH. Abnormalities of neurotransmitter and neuropeptide systems in human neuroepithelioma cells infected by three Toxoplasma strains. J Neural Transm. 2013;120:1631-9). Toxoplasma infection also has effects on the expression of a number of other genes in neural cell cultures and in experimentally infected mice.

  • Effects of T. gondii  infection on GABA

In addition to affecting dopamine, it is now clear that T. gondii  may also affect the GABA neurotransmitter system. GABA is the principal inhibitory neurotransmitter in the brain and is known to be affected in schizophrenia. In 2012, Fuks et al. in Sweden published a study showing that in mice T. gondii  enters the brain and induces an increased production of GABA (Fuks JM, Arrighi RB, Weidner JM, et al. GABAergic signaling is linked to a hypermigratory phenotype in dendritic cells infected by Toxoplasma gondii. PLoS Pathog. 2012;8:e1003051).

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). There are scattered case reports of CNS pathology in adult toxoplasmosis in immunocompetent hosts, such as meningoencephalitis (Kaushik RM, Mahajan SK, Sharma A, et al. Toxoplasmic meningoencephalitis in an immunocompetent host. Trans R Soc Trop Med Hyg. 2005;99:874–878) and brain abscess (Silva LA, Vieira RS, Serafini LN, et al. [Toxoplasmosis of the central nervous system in a patient without immunosuppression: case report]. Rev Soc Bras Med Trop. 2001;34:487–490); however, such reports appear to be rare.

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

In an MRI study of 44 individuals with schizophrenia, it was shown that patients who were seropositive for T. gondii  antibodies had more gray matter reduction than patients who were seronegative (Horacek J, Fleger J, Tintera J, et al. Latent toxoplasmosis reduces gray matter density in schizophrenia but not in controls: Voxel –based-morphometry (VBM) study. World J Biol Psychiatry. 2012;13:501-509). Two histological studies have been done. 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 another study, S.K. Halonen et al. used RT-PCR to look for evidence of T. gondii  in the brain (frontal, parietal and temporal samples) of an individual with schizophrenia who was seropositive; no evidence of T. gondii  was found (Halonen, SK. Final report, Schizophrenia and Toxoplasma gondii  pilot project. Stanley Medical Research Institute. June 2011).

Recent research, not yet published, suggests that the methods used for fixing and freezing postmortem brain tissue may destroy the T. gondii  cysts; if this is true, then it may be virtually impossible to find cysts in human postmortem brain tissue using currently available methods. Other studies of mice have suggested that the number of cysts in the brain decreases over time (Blackwell JM, Roberts CW, Alexander J. Influence of genes within the MHC on mortality and brain cyst development in mice infected with Toxoplasma gondii : kinetics of immune regulation in BALB H-2 congenic mice. Parasite Immunol. 1993;15:317–324; Hunter CA, Roberts CW, Alexander J. Kinetics of cytokine mRNA production in the brains of mice with progressive toxoplasmic encephalitis. Eur J Immunol. 1992;22:2317–2322); this would also make it difficult to find cysts in older tissue.

  • Other means of identifying T. gondii  in brain tissue

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).

 

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).

  • In vitro studies

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). A partial replication of this study was carried out using some different methods and assays. In this study, haloperidol, clozapine and valproic acid had no measurable effect but fluphenazine, thioridazine and trifluoperazine did (Goodwin DG, Strobl J, Mitchell SM, Zajac AM, Lindsay DS. Evaluation of the mood-stabilizing agent valproic acid as a preventative for Toxoplasmosis in mice and activity against tissue cysts in mice. J Parasitol. 2008;94:555-557; Goodwin DG, Strobl JS, Lindsay DS. Evaluation of five antischizophrenic agents against Toxoplasma gondii  in human cell cultures. J Parasitol. 2011;97:148-151). In another replication of this study fluphenazine and zuclopenthixol showed good inhibition of T. gondii; haloperidol, levomepromazine and loxapine showed fair inhibition; and amisulpride, risperidone and valproic acid showed poor inhibition (Fond G, Macgregor A, Tamouza R, et al. Comparative analysis of anti-toxoplasmic activity of antipsychotic drugs and valproate. Eur Arch Psychiatry Clin Neurosci. 2014;264:179-83).

  • 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 FB, Stallings CR, Boronow JJ, et al. A double-blind trial of adjunctive azithromycin in individuals with schizophrenia who are seropositive for Toxoplasma gondii. Schizophr Bull. 2007;112:198–199).

  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 T, Alem A, Abdulahi A, et al. Trimethoprim as adjuvant treatment in schizophrenia: a double-blind, randomized, placebo-controlled clinical trial. Schizophr Bull. 2010;36:846–851).

  Artemisinin: an anti-malarial, was given 200 mg/d or placebo to 66 outpatients with schizophrenia for 10 weeks. There was no significant difference in positive or negative symptoms between groups. However, the artemisinin significantly decreased the level of antibodies to gliadin (p<0.0005) (Dickerson F, Stallings C, Vaughan C, et al. Artemisinin reduces the level of antibodies to gliadin in schizophrenia. Schizophr Res. 2011;129:196–200).

  Artemether: an anti-malarial related to artemisinin, or placebo was given for 8 weeks to 100 individuals with first-episode schizophrenia, all positive for antibodies to T. gondii, in a double-blind study. They were all also taking risperidone. On the PANSS scale for negative symptoms, but not other scales, the patients on artemether improved significantly more than controls (p<0.05) (Wang H, Li Q, Wang X, et al. Clinical trial of artemether in schizophrenia patients with seropositivity to Toxoplasma gondii. J Psych Res. In press).

A major limiting factor in treating humans infected with T. gondii  is that so far no drug has ever been shown to be effective against the cyst stage of the organism, sequestered in the person’s muscles and brain. Research carried out by our colleagues has recently identified promising candidates which are under investigation. These include a derivative of quinolone drugs, widely used to treat malaria, which appears to be effective in inhibiting the toxoplasmosis brain cysts; these drugs are being developed in the laboratory of Mike Riscoe at the University of Oregon.

Another kind of drug being developed for possible use in treating T. gondii  brain infections are analogues of sphingosine, a brain lipid similar to one derived from wild cherry. These are being developed in the laboratory of James McNulty at McMaster University in Ontario (McNulty J, Vemula R, Bordon C, et al. Synthesis and anti-toxoplasmosis activity of 4-arylquinoline-2-carboxylate derivatives. Org Biomol Chem. 2014;12:255-60). One drug in this group, fingolimod, is currently available for the treatment of multiple sclerosis and is undergoing a treatment trial to assess its efficacy in individuals with schizophrenia. Artemisinin derivatives which reduce the burden of T. gondii  brain cysts are also being developed in the laboratory of Vern Carruthers at the University of Michigan (Schultz TL, Hencken CP, Woodard LE, et al. A thiazole derivative of artemisinin moderately reduces Toxoplasma gondii  cyst burden in infected mice. J Parasitol. 2014).


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