(last updated Nov 2012)
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.
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.
provides detailed information on the genome of Toxoplasma gondii
Schizophrenia Research Forum: a
useful online forum to keep updated on schizophrenia research
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.
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.
additional information on schizophrenia, see Torrey EF, Surviving
Schizophrenia, 5th edition (New York, HarperCollins, 2006).
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
V. Studies of T. gondii Antibodies in
VI. Neurotransmitters and T. gondii
VII. Neuropathology of T. gondii
VIII. Treatment Approaches to Toxoplasmosis and
I. All about Cats
felines are the definitive host of T.
gondii, it is useful to know about them.
domestication, and early history
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.
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.
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.
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.
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. 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.
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:
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.
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).
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
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.
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.
and numbers of cats
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).
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).
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.
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).
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).
same researchers calculated the fecal burden by square foot of soil in another
California study. It is known that infected cats can excrete up to 20 million T. gondii oocysts each day during the period they are
infected and that each oocyst can remain viable for a year or longer under
proper climate conditions. Assuming that cats defecated in a completely random
manner, the researchers calculated that each square foot of ground in these
communities would be burdened with between 9 and 434 infected T. gondii oocysts each year (Dabritz et al.). A similar
study was carried out in rural France and arrived at a similar conclusion
regarding the degree of soil contamination by T. gondii oocysts (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;138:1105–1113). Cats, of course, do
not defecate randomly but favor specific outdoor spots, meaning that such spots
are inevitably burdened with a very large number of oocysts (Afonso E, Lemoine
M, Poulle M-L, et al. Spatial distribution of soil contamination by Toxoplasma gondii in relation to cat defecation behaviour
in an urban area. Int J Parasitol. 2008;38:1017–1023).
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
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.
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.
- Ingestion or Inhalation of Oocysts
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. A study
in Brazil reported that school playgrounds in elementary schools were heavily
contaminated by T. gondii oocysts (dos Santos TR, Nunes CM, Luvizotto
MCR, et al. Detection of Toxoplasma
gondii oocysts in environmental
samples from public schools. Vet Parasitol. 2010;171:53–57). Children may
become infected by putting dirty hands, including oocysts, in their mouths. A
family epidemic was described as having occurred this way (Stagno S, Dykes AC,
Amos CS, et al. An outbreak of toxoplasmosis linked to cats. Pediatrics.
1980;65:758–762, copyright 1980, the American Academy of Pediatrics; linked to
PDF file with permission).
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.
(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).
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.
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).
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).
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).
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 recent 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 recent 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).
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?
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.
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?
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:
to 1 yr
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).
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:
to age 13
to age 13
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).
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
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.
III. Epidemiological Similarities and Differences
between Toxoplasmosis and Schizophrenia
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.
areas of similarity are as follows:
and genetic aspects
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.
Toxoplasmosis has also been observed to be familial, affecting multiple members
of the same family, both from having common food exposure and from common
exposure to an infected cat (Stagno S, Dykes AC, Amos CS, et al. An outbreak of
toxoplasmosis linked to cats. Pediatrics. 1980;65:706–712; Sacks JJ, Roberto
RR, Brooks NF. Toxoplasmosis infection associated with raw goat’s milk. JAMA.
1982;248:1728–1732). Animal models of toxoplasmosis have demonstrated that
genes influence the susceptibility of animals to T. gondii infection (Johnson
J, Suzuki Y, Mack D, et al. Genetic analysis of influences on survival
following Toxoplasma gondii infection. Int J Parasitol. 2002;32:179–185;
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).
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).
1. Comparison of age of onset of schizophrenia and toxoplasmosis
of onset of schizophrenia as determined by first admission
of onset of adult toxoplasmosis as determined by lymphadenopathy
get sick at a younger age than females
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).
status and household crowding
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).
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
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).
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).
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
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
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.
low-prevalence toxoplasmosis regions
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).
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).
areas in which epidemiological aspects of toxoplasmosis and schizophrenia are
dissimilar are as follows:
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
high-prevalence toxoplasmosis regions
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.
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
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).
manipulation by T. gondii in rodents
also section VI. Neurotransmitters and T.
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.
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.
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).
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.
of T. gondii on personality traits of humans
Flegr (SMRI grantee) and his colleagues at Charles University in Prague have,
since 1992, been studying the effects of T.
gondii infection on human
personality traits and behavior. Utilizing university students, military
recruits, and blood donors, Flegr et al. have administered a series of
personality questionnaires and compared individuals with and without antibodies
to T. gondii. Infected men were shown
to be more expedient, suspicious, jealous, and dogmatic, whereas infected women
had more warmth and superego strength. 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
of T. gondii on cognition in humans
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 should be performed to further define the association between exposure
to Toxoplasma and cognitive
impairment in other populations, particularly ones containing older adults and
others at risk for cognitive impairment due to multiple genetic and
2. Cognitive functioning in individuals with and without serological evidence
of Toxoplasma infection.
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.
of T. gondii on the behavior of humans
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.
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).
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).
manifestations of congenital T. gondii infections
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).
study has reported psychosis or other symptoms of schizophrenia in children
infected with congenital latent toxoplasmosis. However, a 30-year psychiatric
follow-up of the European cohort cited above reported one case of major
depression, one suicide, and one case of sex change among the eight cases on
which clinical data were available (Selton J-P, Kahn RS. Schizophrenia after
prenatal exposure to Toxomplasma gondii? Clin Infect Dis. 2002;35:633–634).
manifestations of adult T. gondii infections
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.
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).
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).
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).
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.
possible psychiatric manifestation of T.
gondii infection in immunocompetent
hosts is suicidal ideation. One
study in the United States assessed T.
gondii antibodies in 99 individuals
who had made a suicide attempt; 119 individuals with a recurrent mood disorder
but no history of suicide attempts; and 39 unaffected controls. There was no
significant difference in T. gondii seropositivity, but those who had attempted
suicide had higher T. gondii antibody titres (p=0.004) (Arling TA, Yolken
RH, Lapidus M, et al. Toxoplasma gondii antibody titers and history of suicide
attempts in patients with recurrent mood disorders. J Nerv Ment Dis.
2009;197:905–908). The association between suicide attempts and higher titre to
T. gondii antibodies was 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).
Finally, 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).
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.
effects of different strains of T. gondii
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 recent study from our laboratory suggests that type I T. gondii, compared to type II or III, is
more likely to produce psychotic symptoms, especially for affective psychoses
(Xiao J, Buka SL, Cannon TD, et al. Serological pattern consistent with
infection with type I Toxoplasma gondii in mothers and risk of psychosis among adult
offspring. Microbes Infect. 2009;11:1011–1018). 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).
effects of the timing of the initial T.
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
of antibodies in individuals who have schizophrenia
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.
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).
2011 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 2.73 (2.21–3.38) (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.
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).
of antibodies in individuals prior to the onset of schizophrenia
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).
A large study of this military cohort failed to replicate the findings of this
initial study (data not yet published).
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).
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.
of antibodies in newborn children who later develop schizophrenia
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).
of antibodies in maternal sera from late in pregnancy
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
increased antibodies to T. gondii found in other psychiatric and/or neurological
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 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;
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).
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). Finally, a 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
antibodies to T. gondii remain detectable over many years?
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).
VI. Neurotransmitters and T. gondii
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.
of interest in dopamine and T. gondii
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).
gondii has the ability to make dopamine
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).
of changing levels of dopamine on behavior induced by
T. gondii infection
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).
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.
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).
studies on the effect of T. gondii on neurotransmitters being carried out in our
laboratory have shown a differential effect of different strains on
neurotransmitter-related gene expression (Xiao J, not yet published). Toxoplasma infection also has effects on
the expression of a number of other genes in neural cell cultures and in
experimentally infected mice.
VII. Neuropathology of T.
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.
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).
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).
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).
studies of T. gondii in schizophrenia
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. 2011;00:1-9).
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).
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.
means of identifying T. gondii in brain tissue
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
VIII. Treatment Approaches to Toxoplasmosis and
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).
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).
of drugs known to be effective against T.
gondii on patients with
• 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 arithromycin 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.
• 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 symotoms 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.
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 a promising candidate which is under
study for possible trials in humans.