updated Feb 2014)
Welcome to the
Toxoplasmosis–Schizophrenia Research section. This site is maintained by the
Stanley Medical Research Institute (SMRI) and the Stanley
Division of Developmental Neurovirology
for researchers and others interested in the possible etiological relationship
between Toxoplasma gondii (and related organisms) and schizophrenia (and
related psychoses). The purpose of the webpage is to make information on this
line of research, including background data and current research, easily
This section will be updated
periodically. Comments, suggestions, additions, and corrections are welcomed.
They can be sent to either E. Fuller Torrey, MD, or Robert H. Yolken, MD.
ToxoDB: provides detailed information on
the genome of Toxoplasma gondii
Schizophrenia Research Forum: a useful online forum to keep updated on schizophrenia
SMRI has undertaken extensive
research on infectious agents as one of the possible causes of schizophrenia.
Among the infectious agents that appear most promising is Toxoplasma gondii, a protozoan parasite that causes toxoplasmosis
and is carried by cats and other felines. Until recently, toxoplasmosis was
thought to be a problem only for pregnant women who, if they became infected
with T. gondii during their pregnancy, risked having the
organism cause damage to the growing fetus. This is why pregnant women are
advised to not change the litter in the cat litter box. Infection with T. gondii in other adults and children was thought to be
either asymptomatic or to cause an influenza-like or mononucleosis-like
syndrome. It now seems possible that T.
gondii may be associated with
schizophrenia and perhaps other psychiatric syndromes.
Schizophrenia is a brain disease
that begins in young adults, typically between the ages of 16 and 30, and is
characterized by some combination of auditory hallucinations (hearing voices),
delusions, flattened affect, disordered thought patterns, bizarre behavior, and
social withdrawal. Schizophrenia affects approximately 1 percent of the adult population and in most cases is a lifelong disease with
remissions and exacerbations. It is also a very expensive disease. Conservative
estimates place the cost of schizophrenia in the United States at more than $40
billion a year.
For additional information on
schizophrenia, see Torrey EF, Surviving Schizophrenia, 6th edition (New York,
TOPICS OF INTEREST
of T. gondii
Similarities and Differences between Toxoplasmosis and Schizophrenia
of T. gondii on Behavior and Psychiatric Symptoms
of T. gondii Antibodies in Schizophrenia
and T. gondii
of T. gondii
VIII. Treatment Approaches to Toxoplasmosis and Schizophrenia
All about Cats
Since felines are the definitive host of T. gondii, it is useful to know about
- Origin, domestication, and early history
About 12 million years ago, “the felid family underwent an
explosive diversification, giving rise to thirty-seven species that today cover
the Earth’s geographical and ecological spectrum” (Budiansky S. The Character
of Cats. New York: Viking; 2002:6). One of these species was Felis sylvestris,
indigenous to the Middle East, East Asia, and Europe, and the predecessor of
all domestic cats.
Cats were initially domesticated in Turkey, part of the
Fertile Crescent, approximately 10,000 years ago, at the time farming was
beginning (Driscoll CA, Menotti-Raymond M, Roca AL, et al. The Near Eastern
origin of cat domestication. Science. 2007;317:519–523). It is likely that wild
cats were attracted by the mice that accompanied the collections of grain.
Given cat behavior as we know it, it also seems likely that cats domesticated
themselves rather than being domesticated by humans.
From the beginning, cats were very useful to people in
protecting grain and other food supplies, and they continued to be so in this
role until recent years. For example, in 1850 a gold miner in California wrote:
“This evening old Coe came up with our wagons and brought us a cat. Never were
cats in such demand....The whole town is overrun with mice, and they destroy a
deal of property for us....We were at once offered an ounce of gold dust for
every pound the cat weighed” (Bretnor R. Bring cats! A feline history of the
West. The American West. 1978;15:32-35,50).
For most of the time from when cats were initially
domesticated 10,000 years ago until the end of the 18th century CE, cats were
regarded almost exclusively as utilitarian creatures, specifically to kill mice
and rats and thus protect food supplies. There are suggestions they
occasionally were regarded as pets, but except for ancient Egypt, such examples
are rare. For example, in a burial in Cyprus dated to 9,500 years ago, a human
and cat were buried together.
The major example of cats being regarded as pets was in
ancient Egypt when, approximately 3,500 years ago (1,500 BCE), a local cult
worshipping a cat goddess (Bastet) became widespread. Cats were highly valued
and often mummified when they died. DNA sequencing from an Egyptian mummy found
T. gondii DNA sequences in 2013 (Khairat R, Ball M,
Chang CC, et al. First insights into the metagenome of Egyptian mummies using
next-generation sequencing. J Appl Genet. 2013). Herodotus noted the Egyptian
fondness for cats when he visited in 450 BCE. The Egyptians attempted to
restrict the distribution of cats to other countries and prohibited their
The Greeks and Romans kept some cats as mousers, but there
is no evidence that pet-keeping was widespread. Some historians claim that
ferrets were used more commonly than cats to protect the grain. The Romans are
thought to have introduced cats to central and western Europe, including
Britain. Cats are thought to have reached India approximately 2,200 years ago
(200 BCE) and to have reached China and Japan even later. As trade by shipping
became common, cats became essential items on ships to keep the mice, and later
rats, under control, and in this manner cats became geographically
disseminated. References to cats as companions or pets are rare, and “up until
the tenth century the cat is viewed, if not with respect, then with tolerance
and as a necessity and asset to the household” (Lynnlee JL. Purrrfection: The
Cat. West Chester, Pa: Schiffer; 1990:21).
Beginning in the 11th century, tolerance for cats began to
decrease in Europe for religious reasons, and “by the 13th century the church
viewed witches as real and cats as instruments of the devil” (Lynnlee, p. 20).
Dante (1265–1321), for example, mentioned cats only once in his work and
compared them to demons. From the 14th century well into the 18th century, cats
were regularly killed on specific religious holidays. “By the late 15th century
the persecution of cats and witches was a mainstay of European society....The
15th and 16th centuries are almost devoid of any cat literature and
art....During this period the cat still was used to control rodents, but it was
rarely seen as a pet, for if so its existence and that of its owner were in
jeopardy” (Lynnlee, p. 21). Cats became especially associated with heretical
religious sects, such as the Waldensians and Manichaeans, and members of these
sects were accused of worshiping the Devil in the form of a black cat.
On feast days all over Europe, as a symbolic means of
driving out the Devil, they were captured and tortured, tossed onto bonfires,
set alight and chased through the streets, impaled on spits and roasted alive,
burned at the stake, plunged into boiling water, whipped to death, and hurled
from the tops of tall buildings, all in an atmosphere of extreme festive
merriment. (Serpell JA. The domestication and history of the cat. In: Turner DC
and Bateson P, eds. The Domestic Cat. Cambridge: Cambridge University Press;
At Metz, for example, on “cat Wednesday” during Lent, 13
cats were placed in an iron cage and publicly burned; this ritual took place
each year from 1344 to 1777 (Kete K. The Beast in the Boudoir. Berkeley:
University of California Press; 1994:119).
The rehabilitation of cats began in the 18th century, driven
by three things. First was a decline in the belief in witches. Second was the
invasion of Europe by the brown (or gray) rat, which replaced the black rat and
was more prolific and difficult to control. The brown rat reached Germany in
1753, Sweden in 1762, and Switzerland in 1808. Its multiplication was
facilitated by increasing urbanization, and its distribution by increasing sea
travel. Cats were increasingly valued in urban areas and on shipboard. “Many
administrative authorities began to set aside a special budget for the breeding
and maintenance of ratting cats in museums, libraries, prisons, barracks,
warehouses and stores” (Méry F. The Life, History and Magic of the Cat. London:
Paul Hamlyn; 1967:56, 59). Finally, as Pasteur’s work on microbes became well
known, disease became associated with being dirty, and the cat, by virtue of
its cleanliness, was increasingly associated with health.
The earliest modern examples of keeping cats as pets
occurred in the mid-18th century, first in Paris and later in London, among artists
and writers. Cats became associated with intellectuals. By the early 19th
century, descriptions can be found of children playing with cats. Cats began to
be used in advertising in the 1850s, and “some cats were seen on paper fans,
matchbooks, bookmarkers, and the like” (Lynnlee, p. 28). By the 1870s, interest
in cats as pets had become so widespread that writers referred to it as a “cat
fever,” “cat cult,” “cat fancy,” or “cat craze.” “Of late years there has been
a rapid and promising growth of what disaffected and alliterative critics call
the ‘cat cult,’ and poets and painters vie with one another in celebrating the
charms of this long-neglected pet” (Repplier AQ. Agrippina. Atlantic Monthly.
1892;69:760). The first cat show in London took place in the Crystal Palace in
1871; the first show in New York was in Madison Square Garden in 1894.
- Distribution and numbers of cats
As the British colonized the world in the 19th century, they
took their cats with them and thereby introduced cats to Canada, Australia, and
New Zealand. In 1857 in a popular journal, it was noted that “cats have
increased the excitement caused by the arrival of our modern missionaries
amongst an isolated and untaught people” (Anonymous. The cat. Household Words.
1857;15:370). In India cats became popular only among members of the upper
castes who wished to emulate the British. In many other countries, cats were
relatively uncommon and, if they appeared, were regarded as a source of protein
rather than as pets. For example, in 1872 “the enormous amount of rats and
scarcity of cats” was noted in West Africa (Anonymous. Cats. Chamber’s Journal.
Following World War II, cats became very widely distributed
around the world, even in the Arctic. Among five Eskimo villages in Alaska
north of the Arctic Circle, 8 percent of families owned a pet cat in 1974.
Among Skolt Lapps in northern Finland, it was said in 1979 that “practically
each family had at least one cat” (Peterson DR, Cooney MK, Beasley RP.
Prevalence of antibody to Toxoplasma
among Alaskan natives: relation to exposure to the felidae. J Infect Dis.
1974;130:557–563; Huldt G, Lagercrantz R, Sheehe PR. On the epidemiology of
human toxoplasmosis in Scandinavia especially in children. Acta Paediatr Scand.
In recent years, several cities have been said to be heavily
infested with cats. Stockholm has been called the “cat capital of the world,”
and Paris is also said to have large numbers. In the Middle East, Istanbul,
Damascus, and especially Cairo are also said to have many cats, the latter even
having a “cat garden,” originally created by a 13th-century sultan.
In the United States, there
was a 50% increase in owned cats reported between 1989 and 2006 (US Census
Bureau. Surveys by the American Veterinary Medical Association, 1987 and 2006.
In Statistical Abstract of the United
States. U.S. Government Printing Office; 2010). In many American families,
cats have close contact with their owners; one American study reported that 62%
of cats slept with their adult owners and another 13% slept with children (Chomel
BB, Sun B. Zoonoses in the bedroom. Emerg Infect Dis. 2011;17:167-172).
There has also been a
marked increase in recent years in the keeping of cats as pets in developing
countries as people become more affluent. For example, a study of T. gondii oocysts in public parks was also recently
carried out in Wuhan, China (Du F, Feng HL, Nie H, et al. Survey on the
contamination of Toxoplasma gondii oocysts in the soil of public parks of Wuhan,
China. Vet Parasitol. 2012;184:141-146); under the regime of Mao Zedong, the
keeping of pets was considered bourgeois and discouraged. Pet keeping only
started to become prevalent after the death of Mao in 1976 and did not become
common until recent years (Eckholm E. Dog’s life in China: Hiding from police
dragnets. New York Times, 2001; Zhu S. Psychosis may be associated with Toxoplasmosis.
Med Hypotheses. 2009;73:799-801). Yet, when 252 soil samples were taken from
six public parks in Wuhan in 2009 and 2010, 58 samples (23%) contained T. gondii oocysts. The soil samples were taken from
areas frequented by cats. The wider prevalence of T. gondii in modern China is
also reflected in surveys of T. gondii
seropositivity in pregnant women. In
seven studies between 1996 and 2004, the average seropositivity rate was found
to be 4.5%, but in six studies completed since 2004 the average rate was 10.2%
(Zhou P, Chen Z, Li HL, et al. Toxoplasma
gondii infection in humans in China.
Parasit Vectors. 2011;4:165).
Counting cats is notoriously difficult. In the United
States, it has been estimated that there are approximately 90 million pet cats,
which are found in one-third of all households, and an additional 70 million or
more feral cats, thus totaling at least 160 million (Dabritz HA, Conrad, PA.
Cats and Toxoplasma: Implications for
public health. Zoonoses Public Health. 2010;57:34-52). Britain is said to have
about 8 million cats, and Australia to have 20 million, one for every person
(Will G. Millions and millions of cats. Washington Post. July 13, 1997). It is
well known that, left unchecked, cats reproduce rapidly (Kelson L. The race to
outpace feral cat overpopulation. Animal Guardian. 1998;4:8).
Cats excrete the oocysts of T. gondii in their feces for
two to three weeks when they first become infected, usually as kittens or young
cats. This brief two-to-three-week period is generally thought to be the only
time during the life of that cat when it is infectious. There is some evidence,
however, that some cats may later have a reactivation of their T. gondii infection if they are later infected with
other viruses, such as the feline immunodeficiency virus, or are stressed, and
they may excrete oocysts and again become infectious at that time (Hall S, Ryan
M, Buxton D. The epidemiology of Toxoplasma
infection. In Joynson DHM, Wreghitt TG, eds, Toxoplasmosis: A Comprehensive
Clinical Guide. Cambridge: Cambridge University Press; 2004:58–124). At any
given time, it has been estimated that approximately 1 percent of cats are
excreting T. gondii oocysts. One study claimed that “cats can shed
as many as 500 million oocysts” during their initial infection (Dubey JP, Jones
JL. Toxoplasma gondii infection in humans and animals in the
United States. Int J Parasitol. 2008;38:1257–1278). Another recent study of
three communities in California with 12,244 total households reported 7,284
owned and 2,046 feral cats. The annual fecal deposition of these 9,330 cats in
the three communities was estimated to be 106 tons of feces (Dabritz HA, Atwill
ER, Gardner IA, et al. Outdoor fecal deposition by free-roaming cats and
attitudes of cat owners and nonowners toward stray pets, wildlife, and water
pollution. J Am Vet Med Assoc. 2006;229:74–81). Insofar as these
communities are representative of the United States population, the 81.7
million owned cats would produce 856,930 tons of outdoor cat feces each year.
Assuming there are only 25 million feral cats, these would produce another 360
459 tons of cat feces, resulting in a total accumulation of 1,217,389 tons
deposited annually in the environment of the United States (Torrey EF, Yolken
RH. Toxoplasma oocysts as a public
health problem. Trends Parasitol. 2013;29:380-4). A review of this estimate in
the Los Angeles Times claimed that
this weight of cat feces was the equivalent of 12 aircraft carriers (Morin M.
Is your kitty’s poop a public health threat? Los Angeles Times, July 9, 2013).
The oocysts are remarkably
stable, especially if they are deposited in shady, moist, and temperate
conditions. In Texas, under outdoor shaded conditions with a mean air
temperature of 19.5⁰C,
oocysts remained viable during a 13 month experiment (Yilmaz SM, Hopkins SH.
Effects of different conditions on duration of infectivity of Toxoplasma gondii oocysts. J Parasitol. 1972;58:938-9). In
Kansas, oocysts were buried in loose soil and remained viable for 18 months (Frenkel
JK, Ruiz A, Chinchilla M. Soil survival of Toxoplasma
oocysts in Kansas and Costa Rica. Am J Trop Med Hyg. 1975;24:439-43). Oocysts
maintained experimentally at 4⁰C
in seawater or freshwater remained viable for 24 and 54 months, respectively (Dubey
JP. Toxoplasma gondii oocyst survival under defined temperatures. J
Parasitol. 1998;84:862-5, Lindsay DS, Dubey JP. Long-term survival of Toxoplasma gondii sporulated oocysts in seawater. J Parasitol. 2009;95:1019-20).
Oocysts also survived for over a year in vials of 2% sulfuric acid at 4⁰C (Frenkel JK, Dubey JP.
Toxoplasmosis and its prevention in cats and man. J Infect Dis. 1972;126:664-73).
Since almost all of these studies were terminated while at least some of the
oocysts were still viable, we do not yet know the outer limit of viability for T. gondii oocysts deposited in various environmental
Given this large number of T. gondii oocysts, what is the effect of this oocyst
burden on a specific community? In the three California communities cited
above, the T. gondii annual oocyst burden was calculated by
dividing the cat feces by the land area of residential housing. The communities
differed by size and number of cats (Dabritz HA, Atwill ER, Gardner IA, Miller
MA, Conrad PA. Outdoor fecal deposition by free-roaming cats and attitudes of
cat owners and nonowners toward stray pets, wildlife, and water pollution. J Am
Vet Med Assoc. 2006;229:74-81). Depending on estimations of oocyst production
by the cats, the number of T. gondii oocysts ranged from 9 to 434 per square foot (Dabritz
HA, Miller MA, Atwill ER, et al. Detection of Toxoplasma gondii-like oocysts in cat feces and estimates of the
environmental oocyst burden. J Am Vet Med Assoc. 2007;231:1676-84). A similar
study was carried out in three communities in rural France, using comparable
assumptions, and reported that the annual environmental oocyst burden varied
from 3 to 335 oocysts per square foot (Afonso E, Thulliez P, Gilot-Fromont E.
Local meteorological conditions, dynamics of seroconversion to Toxoplasma gondii in cats (Felis catus) and oocyst burden in a
rural environment. Epidemiol Infect. 2010;138:1105-13). In another French
study, T. gondii oocysts were identified in 8 of 62 soil
samples collected from cat defecation sites on the grounds of an urban hospital
(Afonso E, Lemoine M, Poulle ML, et al. Spatial distribution of soil contamination
by Toxoplasma gondii in relation to cat defecation behaviour in an
urban area. Int J Parasitol. 2008;38:1017-23). In Brazil, T. gondii oocysts were
isolated from 10 soil samples taken from the playgrounds of 31 elementary
schools; the authors suggested that these results indicated a wide distribution
of T. gondii oocysts around elementary schools in the
region (dos Santos TR, Nunes CM, Luvizotto MC, et al. Detection of Toxoplasma gondii oocysts in environmental samples from public
schools. Vet Parasitol. 2010;171:53-7). In a village in Panama, it was
estimated that the oocyst burden in soil near houses where cats are fed varied
from 18 to 72 per square foot (Sousa OE, Saenz RE, Frenkel JK. Toxoplasmosis in
Panama: a 10-year study. Am J Trop Med Hyg. 1988;38:315-322). In Poland, T. gondii oocysts were isolated from 18 of 101 soil
samples taken from places thought to be favored by cats for defecation:
sandboxes, playgrounds, parks, gardens, and areas around rubbish pits (Lass A,
Pietkiewicz H, Modzelewska E, Dumètre A, Szostakowska B, Myjak P. Detection of Toxoplasma gondii oocysts in environmental soil samples using
molecular methods. Eur J Clin Microbiol Infect Dis. 2009;28:599-605).
II. Transmission of T. gondii
T. gondii can be acquired by
humans in several different ways. It may be transmitted as a tissue cyst,
usually by eating undercooked meat from an infected animal, or as an oocyst.
- Ingestion of Tissue cysts
of mammals with T. gondii is widespread. Such infections occur when farm
animals ingest feed containing cat feces; when grazing animals inhale or ingest
dried cat feces deposited on the ground; and when an animal eats a smaller
animal, such as a mouse or rat that is infected. T. gondii then invades many
parts of the body, especially muscles, where it becomes tissue cysts and
remains for life. When the muscle is eaten as meat, especially if it has not
been thoroughly cooked, the person becomes infected.
Lamb and pork
are thought to be the most common source of T.
gondii tissue cysts for humans,
although cysts also occur in beef, chicken, and wild animal meat (e.g., deer,
moose, bear). There have even been epidemics of adult toxoplasmosis among
individuals who ate undercooked meat, such as hamburger, from a common source
(Kean BH, Kimball AC, Christenson WN. An epidemic of acute toxoplasmosis. JAMA.
- Ingestion or Inhalation of Oocysts
noted, approximately 1.5 million cats (1 percent of 150 million) in the United
States are excreting oocysts on any given day; they may excrete up to 20
million oocysts per day, and the oocysts may live for a year or longer. Thus,
wherever cats defecate is likely to be a source of contamination. Children’s
play areas and sandboxes are common places for cats to defecate because they
can use the area’s loose soil or sand to bury their feces. Children may become
infected by putting dirty hands, including oocysts, in their mouths. One study of young
children reported that children who are under three years of age put their
hands or other objects in their mouths every 2 to 3 minutes (Black RE, Merson
MH, Huq I, Alim AR, Yunus M. Incidence and severity of rotavirus and Escherichia coli diarrhoea in rural
Bangladesh. Implications for vaccine development. Lancet. 1981;1:141-3).
Another study, which included 64 children between one and four years old,
carried out in a Massachusetts day care center reported that the children
ingested a median of 40 mg of soil per day; furthermore, one child consumed 5
to 8 g of soil per day on average (Calabrese EJ, Barnes R, Stanek EJ 3rd, et
al. How much soil do young children ingest: an epidemiologic study. Regul Toxicol
Pharmacol. 1989;10:123-37). A family
epidemic was described as having occurred this way (Stagno S, Dykes AC, Amos
CS, et al. An outbreak of toxoplasmosis linked to cats. Pediatrics.
1980;65:758–762, copyright 1980, the American Academy of Pediatrics; linked to
PDF file with permission).
As the cat
feces dry, the oocysts may become aerosolized. They can thus be inhaled
by a person changing cat litter or just walking in an area where cats have
defecated. An outbreak of toxoplasmosis among patrons of a riding stable was
thought to have occurred in this manner (Teutsch SM, Juranek DD, Sulzer A, et
al. Epidemic toxoplasmosis associated with infected cats. N Engl J Med.
(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.
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.
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).
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).
importance of different modes of T.
gondii transmission has been
widely debated but minimally studied. In countries like France, which has a
high rate of T. gondii -infected
individuals, the most important source of transmission is thought to be cysts
in undercooked meat. Studies of pregnant women in Europe have identified the
eating of raw or undercooked meat as the most likely source of transmission
(Kapperud G, Jenum PA, Stray-Pedersen B, et al. Risk factors for Toxoplasma gondii infection in pregnancy: results of a
prospective case-control study in Norway. Am J Epidemiology. 1996;144:405–412;
Baril L, Ancelle T, Goulet V, et al. Risk factors for Toxoplasma infection in pregnancy: a case-control study in France.
Scand J Infect Dis. 1999;31:305–309; Cook AJC, Gilbert RE, Buffolano W, et al.
Sources of Toxoplasma infection in
pregnant women: European multicentre case-control study. Br Med J.
2000;321:142–147). In countries like the United States, in which meat is
generally well cooked, direct transmission of oocysts from cats especially via
water, and contaminated fruits and vegetables, is thought to be more important
(Boyer K, Hill D, Mui, E, et al. Unrecognized ingestion of Toxoplasma gondii oocysts
leads to congenital toxoplasmosis and causes epidemics in North America. Clin
Infect Dis. 2011;53:1081-9). Recent studies have reported that the majority of
congenital infections (Boyer K, Hill D, Mui E, et al. Unrecognized ingestion of
Toxoplasma gondii oocysts leads to congenital toxoplasmosis and
causes epidemics in North America. Clin Infect Dis. 2011;53:1081-9) and
postnatal acute infections (Hill D, Coss C, Dubey JP, et al. Identification of
a sporozoite-specific antigen from Toxoplasma
gondii. J Parasitol. 2011;97:328-37) in the United States are from oocysts.
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
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.
Transmission of T. gondii
A study in
dogs demonstrated that T. gondii can
be transmitted sexually in that species. Male dogs were infected by T.
gondii ; it was then found in their semen. The infected semen was then used
to artificially inseminate four uninfected female dogs. Seven days after
insemination, all four dogs had antibodies to T. gondii. Two of the
pregnant dogs had miscarriages; the other two delivered four puppies, none of
whom lived longer than three weeks and all of which had cysts containing T.
gondii in their brains (Arantes TP,
Lopes WD, Ferreira RM, et al. Toxoplasma
gondii : evidence for the transmission by semen in dogs. Exp Parasitol.
2009;123:190–194). Another study demonstrated that T. gondii can be sexually transmitted in rats; 43 of 69
rat pup offspring, following sexual transmission, were found to be infected
(Dass SAH, Vasudevan A, Dutta D, et al. Protozoan parasite Toxoplasma gondii
manipulate mate choice in rats by
enhancing attractiveness of males. PLoS One. 2011;11:e27229.
doi:10.1371/journal.pone.0027229). Most recently, it was demonstrated that T. gondii can be sexually transmitted in sheep; infected
males were able to infect previously-uninfected females and the infection was
then transmitted vertically to their lambs (Lopes WDZ, Rodriguez JD, Souza FA,
et al. Sexual transmission of Toxoplasma
gondii in sheep. Vet Parasitol.
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).
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).
people with close cat contact have a greater chance of being infected with
previously, T. gondii can be transmitted from cats to humans in many
different ways. Being bitten by a cat, however, apparently does not cause the
transmission of T. gondii (Westling K, Jorup-Ronstrom C, Evengard B.
Toxoplasmosis not transmitted by cat bite, but high prevalence of antibodies to
Toxoplasma gondii in patients bitten by their own cat. Scand J
Infect Dis. 2010;42:687–690). Some of the means of transmission require no
contact whatever between cats and humans, e.g., through tissue cysts in
undercooked lamb, drinking water infected with oocysts, oocysts deposited by a
neighborhood cat in your garden. For this reason, attempts to show a
correlation between having antibodies to T.
gondii and past contact with cats
have yielded very inconsistent results.
A review of 30
such studies reported that half of them found a correlation, but half did not
(Hall S, Ryan M, Buxton D. The epidemiology of Toxoplasma infection. In Joynson DHM, Wreghitt TG, eds,
Toxoplasmosis: A Comprehensive Clinical Guide, Cambridge: Cambridge University
Press; 2001:85–91). Those studies that were negative were more likely to have
been studies of adults, e.g., pregnant women who were asked if they presently
owned a cat. Those studies that were positive were more likely to have included
children and teenagers, such as studies done in Costa Rica and Panama (Sousa
OE, Saenz RD, Frenkel JK. Toxoplasmosis in Panama: a 10-year study. Am J Trop
Med Hyg. 1988;38:315–322; Frenkel JK, Ruiz A. Human toxoplasmosis and cat
contact in Costa Rica. Am J Trop Med Hyg. 1980;29:1167–1180). The results
varied depending on how the question was asked, with cat ownership in childhood
more likely to yield a positive correlation with T. gondii antibodies than
cat ownership in adulthood. The complexity of studying human–cat contact was
also illustrated by a Norwegian study that asked about cat contact in great
detail. Becoming infected with T. gondii was not statistically related to “living in a
neighborhood with a cat” (p=0.71) or “living in a household with a cat”
(p=0.13) but was statistically significantly related to “living in a household
with a kitten less than 1 year old” (p=0.04) (Kapperud G, Jenum PA,
Stray-Pedersen, et al. Risk factors for Toxoplasma
gondii infection in pregnancy:
results of a prospective case-control study in Norway. Am J Epidemiol.
1966;144:405–412). An American study reported that living in a household with
one or two kittens was not a significant risk factor for becoming infected with
T. gondii, but living in a household
with three or more kittens was a highly significant risk factor (OR 35.4)
(Jones JL, Dargelas V, Roberts J, et al. Risk factors for Toxoplasma gondii infection
in the United States. Clin Infect Dis. 2009;49:878–884).
children with close cat contact have a greater chance of developing
In view of the
above, it is of interest that two studies that have assessed cat contact during
childhood reported that it was significantly more common in individuals with
schizophrenia than in controls. In the first study of 165 parents of
individuals with schizophrenia and bipolar disorder, 51 percent reported that
they owned a cat during pregnancy or during the first 10 years of life of the
affected individuals, compared to 38 percent among matched controls (p=0.02,
chi square; however, this was not corrected for the number of questions asked,
which would require a p<0.01 using a Bonferroni correction). The question
was asked for four different periods, and the results were as follows:
to 1 yr
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).
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
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).
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
A few of the T. gondii antibody studies (see section V) have also
collected information on cat exposure. For example, a Turkish study of 73
patients with first-episode schizophrenia and 40 controls reported that 15/73
(28%) of the patients had a cat in their house compared to 1/40 (3%) of the
controls (p=0.006) (Tanyuksel M, Uzun O, Araz E, et al. Possible role of
toxoplasmosis in patients with first-episode schizophrenia. Turk J Med Sci.
Similarities and Differences
there are at least eight areas of similarity between toxoplasmosis and
schizophrenia. There are also at least three areas in which epidemiological
aspects are dissimilar.
The areas of
similarity are as follows:
and genetic aspects
The fact that
schizophrenia is familial, as demonstrated by family, twin, and adoption
studies, is one of the most salient features of this disease. The explanation
for this familial pattern is widely assumed to be genetic, and more than one
hundred candidate predisposing genes have been identified. Many of the
candidate genes predisposing to schizophrenia have been shown to be activated
by Toxoplasma infection in cell
cultures and in experimental animals. (For a detailed analysis of the effect of
T. gondii on genes which have been linked to
schizophrenia see Carter CJ. Toxoplasmosis and polygenic disease susceptibility
genes: Extensive Toxoplasma gondii host/pathogen interactome enrichment in nine
psychiatric or neurological disorders. J Pathogens. 2013;2013:965046). Of
particular importance was the activation of microRNAs such as mi132 and mi137
since these microRNAs have been implicated in schizophrenia by genetic studies.
has also been observed to be familial but not necessarily for genetic reasons.
A familial pattern to the disease has been observed, both from having common
food exposure and from common exposure to an infected cat (Stagno S, Dykes AC,
Amos CS, et al. An outbreak of toxoplasmosis linked to cats. Pediatrics.
1980;65:706–712; Sacks JJ, Roberto RR, Brooks NF. Toxoplasmosis infection
associated with raw goat’s milk. JAMA. 1982;248:1728–1732). In one study of
family transmission, it was found that in half of the families in which one
person becomes infected with acute toxoplasmosis, as second member of the
family also becomes infected (Contopoulos-loannidis DG, Maldonado Y, Montoya
JG. Acute Toxoplasma gondii infection among family members in the
United States. Emerg Infect Dis. 2013;19:1981-1984. Animal models of
toxoplasmosis have demonstrated that genes influence the susceptibility of
animals to T. gondii infection (Johnson J, Suzuki Y, Mack D, et al.
Genetic analysis of influences on survival following Toxoplasma gondii infection.
Int J Parasitol. 2002;32:179–185; Blackwell JM, Roberts CW, Alexander J.
Influence of genes within the MHC on mortality and brain cyst development in
mice infected with Toxoplasma gondii :
kinetics of immune regulation in BALB H-2 congenic mice. Parasite Immunol.
1993;15:317–324). It is also known that mice with chronic T. gondii infections can
pass the infection to their offspring for as many as five successive
generations in a pseudogenetic pattern (Beverley JKA. Congenital transmission
of toxoplasmosis through successive generations of mice [letter]. Nature.
1959;183:1348–1349; Owen MR and Trees AJ. Vertical transmission of Toxoplasma gondii from chronically infected house [Mus musculus]
and field [Apodemus sylvaticus] mice determined by polymerase chain reaction.
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
Age of onset of schizophrenia as determined by first admission
Age of onset of adult toxoplasmosis as determined by lymphadenopathy
get sick at a younger age than females
It is clearly
established that males develop schizophrenia at an average younger age than
females. In studies done in England, the mean age at first admission for
schizophrenia was 28.0 for males and 31.8 for females (Watt DC, Szulecka TK.
The effect of sex, marriage and age at first admission on the hospitalization
of schizophrenics during 2 years following discharge. Psychol Med.
1979;9:529–539). The pattern is similar for adult-onset toxoplasmosis; in one
study, the mean age of onset was 27.7 for males and 31.9 for females (Ryan M,
Hall SM, Barrett NJ, et al. Toxoplasmosis in England and Wales 1981 to 1992.
Commun Dis Rep CDR Rev. 1995;5:R13–21). In another study, three times more males
than females became infected under age 15 (Beverley JKA, Fleck DG, Kwantes W.
Age-sex distribution of various diseases with particular reference to
toxoplasmic lymphadenopathy. J Hyg (Camb). 1976;76:215–228).
status and household crowding
In the United
States, studies have demonstrated that the prevalence of schizophrenia is
higher in individuals who are poorer and who live in more crowded households
(Regier DA, Farmer ME, Rae DS, et al. One-month prevalence of mental disorders
in the United States and sociodemographic characteristics: the Epidemiologic
Catchment Area study. Acta Psychiatr Scand. 1993;88:35–47; Schweitzer L and Su
E-H. Population density and the rate of mental illness. Am J Public Health.
1977;67:1165–1172). Similarly, the prevalence of antibodies to T. gondii has been shown to be higher in individuals who
are poorer and who live in more crowded households (Kruszon-Moran D, McQuillan
GM. Seroprevalence of six infectious diseases among adults in the United States
by race/ethnicity: data from the third National Health and Nutrition
Examination Survey. Adv Data. 2005;352:1–9).
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
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).
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).
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
An increase in
stillbirths among mothers with schizophrenia has been reported in five studies
(Sobel DE. Infant mortality and malformations in children of schizophrenic
women. Psychiatr Q. 1961;35:60–65; Rieder RO, Rosenthal D, Wender P, et al. The
offspring of schizophrenics: fetal and neonatal deaths. Arch Gen Psychiatry.
1975;32:200–211; Modrzewska K. The offspring of schizophrenic parents in a North
Swedish isolate. Clin Genet. 1980;17:191–201; Nilsson E, Lichtenstein P,
Cnattingius S, et al. Women with schizophrenia: pregnancy outcome and infant
death among their offspring. Schizophr Res. 2002;58:221–229; Bennedsen BE,
Mortensen PB, Olesen AV, et al. Congenital malformations, stillbirths, and
infant deaths among children of women with schizophrenia. Arch Gen Psychiatry.
2001;58:674–679). However, it was not found in a sixth study (Jablensky AV,
Morgan V, Zubrick SR, et al. Pregnancy, delivery, and neonatal complications in
a population cohort of women with schizophrenia and major affective disorders.
Am J Psychiatry. 2005;162:79–91). An increase in stillbirths has also been
documented among women infected with T.
gondii during pregnancy (Sever JL,
Ellenberg JH, Ley AC, et al. Toxoplasmosis: maternal and pediatric findings in
23,000 pregnancies. Pediatrics. 1988;82:181–192).
low-prevalence toxoplasmosis regions
As has been
demonstrated on isolated islands, toxoplasmosis does not exist in places where
there are no felines. In areas where felines are rare, the prevalence rates of
both toxoplasmosis and schizophrenia appear to be low. The best example is
probably the highlands of Papua New Guinea, where until recently, domesticated
cats were virtually nonexistent and wild felines comparatively rare. In this
area, the percentage of people with antibodies to T. gondii was reported to be
2 percent or less (Wallace GD, Zigas V, Gajdusek DC. Toxoplasmosis and cats in
New Guinea. Am J Trop Med Hyg. 1974;23:8–14). A 1973 study of the prevalence of
schizophrenia in this area also reported it to be among the lowest in the world
(Torrey EF, Torrey BB, Burton-Bradley BG. The epidemiology of schizophrenia in
Papua New Guinea. Am J Psychiatry. 1974;131:567–572).
were kept as pets in ancient Egypt, their modern domestication began only in
the mid-eighteenth century and then increased rapidly (Champfleury M. The Cat:
Past and Present. London: George Bell & Sons; 1885). Some people believe
that schizophrenia was a rare disease prior to the mid-eighteenth century but
then increased rapidly in incidence. Thus, the increase in keeping cats as pets
and the increase in schizophrenia would have coincided (Torrey EF and Miller J.
The Invisible Plague: The Rise of Mental Illness from 1750 to the Present. New
Brunswick, N.J.: Rutgers University Press; 2001).
The areas in which epidemiological aspects of toxoplasmosis
and schizophrenia are unclear or dissimilar are as follows:
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.
multiple reports that the seroprevalence of toxoplasmosis has decreased sharply
in the United States and Europe in the past forty years (Jones JL,
Kruszon-Moran D, Sanders-Lewis K, et al. Toxoplasma
gondii infection in the United
States, 1999–2004, decline from the prior decade. Am J Trop Med Hyg.
2007;77:405–410). It has been speculated that this is because of the increased
use of frozen meat, since freezing kills the tissue cysts, and better food
hygiene in general (Forsgren M, Gille E, Ljungström I, et al. Toxoplasma gondii in pregnant women in Stockholm in 1969, 1979,
and 1987 [letter]. Lancet. 1991;337:1413–1414; Walker J, Nokes DJ, Jennings R.
Longitudinal study of Toxoplasma
seroprevalence in South Yorkshire. Epidemiol Infect. 1992;108:99–106; Jones JL,
Kruszon-Moran D, Sanders-Lewis K, et al. Toxoplasma
gondii infection in the United
States, 1999–2004, decline from the prior decade. Am J Trop Med Hyg.
2007;77:405–410). By contrast, there are no reports of a sharp decrease in the
prevalence of schizophrenia in either the United States or Europe.
IV. Effects of T. gondii on Behavior and Psychiatric
the late 1970s, G. Piekarski (1978) and P.-A. Witting (1979) in Bonn began
investigations to ascertain possible effects of latent T. gondii on mice and rats.
The impetus for their research appears to have been the reported behavioral
effects of other parasitic infections and the known association of congenital T. gondii with mental retardation. Piekarski and Witting
reported that T. gondii caused impaired learning in mice and rats and
impaired memory in mice. Based on these findings, Hutchinson, Hay et al. in
Glasgow studied T. gondii –infected
mice and reported that, compared to uninfected controls, the infected mice had
increased activity, especially in exploring novel environments. Holliman
summarized this early research (Holliman RE. Toxoplasmosis, behaviour and
personality. J Infect. 1997;35:105–110). Much subsequent work has been carried
out in rodents; see, for example, Kannan G, Pletnikov MV. Toxoplasma gondii and
cognitive deficits in schizophrenia: An animal model perspective. Schizophr
manipulation by T. gondii in rodents
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.
(SMRI grantee) and her colleagues, initially at Oxford and now at Imperial
College London, noted the early research cited above and carried it forward.
Beginning in 1994, they published a series of studies demonstrating that rats
infected with T. gondii were more active and less neophobic of cat
urine than controls rats (Berdoy M, Webster JP, Macdonald DW. Fatal attraction
in rats infected with Toxoplasma gondii.
Proc R Soc Lond B. 2000;267:1591–1594). Both changes would make it more likely that
the rat would be eaten by a cat, thus completing the life cycle of T. gondii and being an example of the manipulation
hypothesis. These studies were summarized by Dr. Webster (Webster JP. Rats,
cats, people and parasites: the impact of latent toxoplasmosis on behavior.
Microbes Infect. 2001;3:1037–1045). Webster and Glenn McConkey have also
speculated about specific mechanisms that may explain the parasite manipulation
(Webster JP, McConkey GA. Toxoplasma
gondii -altered behaviour: clues as to mechanism of action. Folia
Parasitol. 2010;57:95–104). A recent summary of this work is Webster JP,
Kaushik M, Bristow GC, McConkey GA. Toxoplasma
gondii infection, from predation to
schizophrenia: can animal behavior help us understand human behavior? J Exp
Biol. 2013;216:99-112 and Kaushik M, Lamberton PHL, Webster JP. The role of
parasites and pathogens in influencing generalized anxiety and
predation-related fear in the mammalian central nervous system. Horm Behav.
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).
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.
interesting example of the effects of T.
gondii on animal behavior is the sea
otters who live on the coast of California. Many have become infected with T. gondii, presumably because of
rainwater runoff from cat-infested areas carrying the oocysts into the ocean. A
2004 study reported that sea otters with toxoplasmosis were 3.7 times more
likely to be attacked by sharks than others who were not infected (Miller MA,
Grigg ME, Kreuder C, et al. An unusual genotype of Toxoplasma gondii is common
in California sea otters (Enhydra lutris
nereis) and is a cause of mortality. Int J Parasitol. 2004;34:275-84.
of T. gondii on personality traits of humans
() and his colleagues at Charles University in Prague have, since 1992, been
studying the effects of T. gondii infection on human personality traits and
behavior. Utilizing university students, military recruits, and blood donors,
Flegr et al. have administered a series of personality questionnaires and
compared individuals with and without antibodies to T. gondii. Infected men were shown to be more expedient,
suspicious, jealous, and dogmatic, whereas infected women had more warmth and
superego strength. Thus, sex differences of the effect of T. gondii in humans have
been shown, just as they have been in rodents. Flegr has summarized these
findings (Flegr J. Effects of Toxoplasma
on human behavior. Schizophr Bull. 2007;33:757–760; Flegr J. Influence of
latent toxoplasmosis on the phenotype of intermediate hosts. Folia Parasitol.
2010;57:81–87). An article describing Flegr’s research was also published in
the Atlantic magazine (McAuliff K.
How your cat is making you crazy. March 2012).
of T. gondii on cognition in humans
The effects of
T. gondii on cognitive measures in humans has been
studied by our laboratory (Yolken RH, Dickerson FB, Torrey EF. Toxoplasma and schizophrenia. Parasite
Immunol. 2009;31:706–715). We measured Toxoplasma
IgG antibodies and cognitive functioning in 291 individuals between the ages of
19 and 60 who did not have a history of a psychiatric disorder. As depicted in
Figure 2, we found that individuals with serological evidence of Toxoplasma infection had significantly
worse performance in measures of delayed memory (p<0.002) and immediate
memory (p<0.05) and trends toward worse performance in other domains. On the
other hand, Toxoplasma serostatus was
not associated with demographic variables that might affect the results of
cognitive testing such as age, gender, race, or level of education. Additional
studies have been performed to further define the association between exposure
to Toxoplasma and cognitive
impairment in other populations.
2. Cognitive functioning in individuals with and without serological evidence
of Toxoplasma infection.
A total of 291
individuals between the ages of 19 and 60 without a history of a psychiatric
disease underwent cognitive testing and had their serum IgG antibodies measured
to Toxoplasma gondii. A total of 39
(13.4%) of the individuals had serological evidence of Toxoplasma infection as defined by antibody levels > 10 international units. The bars indicate the mean
performance on cognitive tasks with the results standardized so that the mean
value in the Toxoplasma seronegative
group is equal to one. The error bars indicate the 95% confidence intervals of
the mean values. The tests performed are as follows: Del Mem, RBANS Delayed
Memory; Imm Mem, RBANS Immediate Memory; Vis Con, RBANS
Visuospatial/Constructional; Attent, RBANS Attention; Lang., RBANS Language;
RBANS Tot, RBANS Total Score; WCS Per Err, Wisconsin Card Sorting Task
perseverative errors; WCS Comp, Wisconsin Card Sorting Task categories
completed; Let Num Sc, Letter Number test scaled score; Trial Sc, Trail Making
Test A scaled score. The indicated p values are computed from linear regression
models that include age, gender, race, and level of education.
A study in
Brazil carried out in 100 schoolchildren reported that the children infected
with T. gondii did more poorly on some academic tests,
especially in mathematics (Ferreira EC, Marchioro AA, Guedes TA, et al. Association
between seropositivity for Toxoplasma
gondii, scholastic development of children and risk factors for T. gondii infection. Trans R Soc Trop Med Hyg.
2013;107:390-6). Other studies carried out in healthy elderly individuals have
reported that infection with T. gondii is associated with greater memory impairment (Gajewski
PD, Falkenstein M, Hengstler JG, Golka K. Toxoplasma
gondii impairs memory in infected
seniors. Brain Behav Immun. 2014;36:193-9) and deficits in goal-directed
behavior (Beste C, Getzmann S, Gajewski PD, Golka K, Falkenstein M. Latent Toxoplasma gondii infection leads to deficits in goal-directed
behavior in healthy elderly. Neurobiol Aging. 2014;35:1037-44).
of T. gondii on the behavior of humans
Flegr et al. also
compared his infected and uninfected human subjects on reaction time as
measured by a standard computerized test. Infected individuals performed
significantly more poorly and appeared to lose their concentration more quickly
(Havlicek J, Gasova Z, Smith AP, et al. Decrease in psychomotor performance in
subjects with latent ‘asymptomatic’ toxoplasmosis. Parasitology.
2001;122:515–520). Pearce et al. also demonstrated psychomotor slowing in
healthy humans, as well as in those with schizophrenia, who were infected with T. gondii compared with those not infected (Pearce BD,
Hubbard S, Rivera HN, et al. Toxoplasma
gondii exposure affects neural
processing speed as measured by acoustic startle latency in schizophrenia and
controls. Schizophr Res. 2013;150:258-61.
Flegr et al.
also compared the sera of 146 individuals deemed to have been responsible for
causing a motor vehicle accident, with 446 controls. Those individuals who had
antibodies to T. gondii, compared
with those without antibodies, had more than twice the risk of having caused a
motor vehicle accident (Flegr J, Havlicek J, Kodym P, et al. Increased risk of
traffic accidents in subjects with latent toxoplasmosis: a retrospective
case-control study. BMC Infect Dis. 2002;2:11). This research group
subsequently replicated this finding in another driver cohort in the Czech
Republic (Flegr J, Klose J, Novotna M, et al. Increased incidence of traffic
accidents in Toxoplasma-infected
military drivers and protective effect RhD molecule revealed by a large-scale
prospective cohort study. BMC Infect Dis. 2009;9:e72).
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.
It is clearly
established that congenital infections with T.
gondii, especially early in pregnancy, can produce intracranial
calcifications, mental retardation, deafness, seizures, and retinal damage.
Less clearly established are the long-term effects of congenital infection that
occur late in pregnancy and that are often latent at birth. Two research groups
have reported late effects, especially lower IQ, following latent congenital
infections (Alford A, Stagno S, Reynolds DW. Congenital toxoplasmosis:
clinical, laboratory, and therapeutic considerations, with special reference to
subclinical disease. Bull NY Acad Med. 1974;50:160–181; Wilson CB, Remington
JS, Stagno S, et al. Development of adverse sequelae in children born with
subclinical congenital Toxoplasma
infection. Pediatrics. 1980;66:767–774). However, long-term follow-up of a
similar cohort in Europe reported no loss of IQ or other significant sequelae
(Koppe JG, Rothova A. Congenital toxoplasmosis: a long-term follow-up of 20
years. Int Ophthalmol. 1989;13:387–390).
No study has
reported psychosis or other symptoms of schizophrenia in children infected with
congenital latent toxoplasmosis. Rima McLeod, who has followed large numbers of
such children over many years, reported that among the congenitally-infected
cases “there have been only rare persons with these neuropsychiatric or other
disease” (McLeod R, VanTubbergen C, Montoya JG, et al. Human toxoplasmosis
infection. In LM Weiss and K Kim, eds., Toxoplasma
gondii. Amsterdam:Elsevier;2013:109). However, a 30-year psychiatric
follow-up of the European cohort cited above reported one case of major
depression, one suicide, and one case of sex change among the eight cases on
which clinical data were available (Selton J-P, Kahn RS. Schizophrenia after
prenatal exposure to Toxomplasma gondii? Clin Infect Dis. 2002;35:633–634).
manifestations of adult T. gondii infections
become infected with T. gondii at any time in life. In immunocompetent
individuals, the infection is asymptomatic 90 percent of the time. In the other
10 percent, the "primary infections cause a mild, mononucleosis-like
illness with low-grade fever, malaise, headache, and cervical lymphadenopathy"
(Kravetz JD. Toxoplasma gondii. In:
Fratamico PM, Smith JL, Brogden KA, eds, Sequelae and Long-Term Consequences of
Infectious Diseases. Washington, D.C.: ASM Press; 2009:217–228). The clinical
picture is nonspecific but often includes headache, fever, malaise, myalgia,
and lymphadenopathy (Carme B, Demar M, Ajzenberg D, et al. Severe acquired
toxoplasmosis caused by wild cycle of Toxoplasma
gondii, French Guiana. Emerg Infect Dis. 2009;15:656-658; Silva CS, Neves
ES, Benchimiol EL, et al. Postnatal acquired toxoplasmosis patients in an
infectious disease reference center. Braz J Infect Dis. 2008;12:438-441). In
recent years, most clinical cases have been described in patients with AIDS,
thus making it difficult to ascertain which clinical symptoms are due to the
toxoplasmosis and which are due to AIDS. However, in 1966, prior the AIDS
epidemic, two publications summarized the neurological and psychiatric symptoms
found in T. gondii infection occurring in adults.
Kramer in the
Netherlands summarized 114 cases of symptomatic adult toxoplasmosis published
between 1940 and 1964. Among these, he noted that “psychiatric disturbances
were very frequent,” occurring in 24 cases. Some cases were described as having
acute or subacute psychosis, and others as having “psychic alteration” (Kramer
W. Frontiers of neurological diagnosis in acquired toxoplasmosis. Psychiatr
Neurol Neurochir. 1966;69:43–64). Ladee et al., also in the Netherlands, noted
that “the literature not infrequently focuses attention on psychoses with
schizophrenic or schizophreniform features that accompany chronic toxoplasmosis
or that acquired in childhood or early in adult life. . . . In several
instances a neurasthenic prodromal stage is followed by an initially suspected
paranoid or paranoid-hallucinatory picture” (Ladee GA, Scholten JM, Meyes FEP.
Diagnostic problems in psychiatry with regard to acquired toxoplasmosis.
Psychiatr Neurol Neurochir. 1966;69:65–82).
Many of these
early reported cases are very interesting. For example, in 1951 Ström reported
two cases of adult toxoplasmosis in laboratory workers. A 22-year-old woman who
“often pipetted toxoplasma exudates” developed lyphadenopathy, headache, and
fever. Diagnosis of toxoplasmosis was confirmed by skin test. Attempts to demonstrate
T. gondii by microscopy of CSF or inoculation of CSF
into mice was unsuccessful. She also had psychiatric symptoms: three months
after the onset of infection, she “finds it difficult to concentrate,” “cannot
follow a conversation when several people are present,” and “she feels far
away, as if her body wasn’t there” (Ström J. Toxoplasmosis due to laboratory
infection in two adults. Acta Med Scand. 1951;139:244–252).
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).
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). A recent study of 156 suicide attempters and 127 controls in
Mexico reported similar results. There was no statistical difference in
seropositivity but the titers of the T. gondii
antibody was significantly higher
(p=0.04) in the suicide attempters (Alvarado-Esquivel C, Sánchez-Anguiano LF,
Arnaud-Gil CA, et al. Toxoplasma gondii infection and suicide attempts: A case-control
study in psychiatric outpatients. J Nerv Ment Dis. 2013;201:948-52). The
association between suicide attempts and higher titre to T. gondii antibodies was
replicated by a study in Turkey (Yagmur F, Yazar S, Temel HO, et al. May Toxoplasma gondii increase suicide attempt-preliminary results
in Turkish subjects? Forensic Sci Int. 2010;199:15-17). A third study reported
an association between suicide attempts and T.
gondii seropositivity in patients
with schizophrenia, but the association was only significant in younger
patients (Okusaga O, Langenberg P, Sleemi A, et al. Toxoplasma gondii antibody
titers and history of suicide attempts in patients with schizophrenia.
Schizophr Res. 2011;133:150-155). In 2012 a Danish study reported that women
who were infected with T.gondii were significantly more likely to be suicidal
and twice as likely to successfully commit suicide, compared to women not
infected (Pedersen MG, Mortensen PB, Norgaard-Pedersen B, Postolache TT. Toxoplasma gondii infection and self-directed violence in
mothers. Arch Gen Psychiatry. 2012;doi:10.1001/archgenpsychiatry.2012.668) and in
Sweden, a study of 54 adult suicide attempters reported increased
seropositivity of T. gondii (OR 7.12, p=0.08) compared to controls (Zhang
Y, Träskman-Bendz L, Janelidze S, et al. Toxoplasma
gondii immunoglobulin G antibodies
and nonfatal suicidal self-directed violence. J Clin Psychiatry.
2012;73:1069-76). Finally, a study of national suicide rates in 17 European
nations reported a significant association between the prevalence of T. gondii and the suicide rate (Lester D. Predicting
European suicide rates with physiological indices. Psychol Rep. 2010;107:713-4).
studies are of interests regarding the effect of T. gondii on behavior and
psychiatric symptoms. Holub and his colleagues in Prague divided individuals
with schizophrenia into those with antibodies to T. gondii (n=57) and those
without such antibodies (n=194), then retrospectively assessed their clinical histories.
The patients with antibodies were found to have had an earlier onset of their
illness for men, but not women; to have more severe symptoms; and to have been
hospitalized for longer (Holub D, Flegr J, Dragomirecká E, et al. Differences
in onset of disease and severity of psychopathology between
toxoplasmosis-related and toxoplasmosis-unrelated schizophrenia. Acta Psychiatr
of interest was the effect of seropositivity to T. gondii on the mortality
rate of individuals with schizophrenia. In an earlier study, Dickerson et al.
reported that antibodies for T. gondii were associated with an increased mortality (Dickerson
F, Boronow J, Stallings C, Origoni A, Yolken R. Toxoplasma gondii in
individuals with schizophrenia: Association with clinical and demographic
factors and with mortality. Schizophr Bull. 2007;33:737-40). However, a later
study reported that this relationship was no longer statistically significant
when it was corrected for age and gender (Dickerson F, Stallings C, Origoni A,
Schroeder J, Khushalani S, Yolken R. Mortality in Schizophrenia: Clinical and
Serological Predictors. Schizophr Bull. 2013 Aug 13). Finally, a demographic
study reported a correlation between the prevalence of T. gondii and the national
homicide rate in 20 European nations for the year 2000 (Lester D. Toxoplasma gondii and homicide. Psychol Rep. 2012;111:196-7).
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.
least 15 distinct strains of T. gondii are known, most isolates of T. gondii in Europe and North America belong to one of
three strains: I, II, or III. Despite having more than 98 percent genetic
identity, the effects of the three strains are quite different in rodents and
are assumed to be so in humans as well. In mice, for example, the three strains
produce significantly different gene expression (Hill RD, Gouffon JS, Saxton
AM, Su C. Differential gene expression in mice infected with distinct Toxoplasma strains. Infect Immun.
2012;80(3):968-74). Studies of the three strains on gene expression in human
neuroepithelial cells also show markedly different effects on gene expression,
with type I exhibiting the highest level of gene expression (Xiao J,
Jones-Brando L, Talbot CC Jr, et al. Differential effects of three canonical Toxoplasma strains on gene expression in
human neuroepithelial cells. Infect Immun. 2011;79:1363–1373). It has also been
shown that different strains of T. gondii
produce different effects on mouse
behavior (Kannan G, Moldovan K, Xiao J-C, et al. Toxoplasma gondii strain-dependent effects on mouse behavior.
Folia Parasitol. 2010;57:151–155). Similarly, it is known that type I T. gondii is much more lethal in mice than type II or
type III, but it was not known whether or not this also applies to human
infections. A study from our laboratory suggests that type I T. gondii, compared to type II or III,
is more likely to produce psychotic symptoms, especially for affective
psychoses (Xiao J, Buka SL, Cannon TD, et al. Serological pattern consistent
with infection with type I Toxoplasma
gondii in mothers and risk of
psychosis among adult offspring. Microbes Infect. 2009;11:1011–1018). Another
study from our laboratory showed that the different strains of T. gondii had very different effects on neurotrasmitters
(Xiao J, Li Y, Jones-Brando L, Yolken RH. Abnormalities of neurotransmitter and
neuropeptide systems in human neuroepithelioma cells infected by three Toxoplasma strains. J Neural Transm.
2013;120:1631-9). In a related study, in human congenital T. gondii infections,
different strains of T. gondii were found to produce differences in the
incidence of premature births and eye disease (McLeod R, Boyer KM, Lee D, et
al. Prematurity and severity are associated with Toxoplasma gondii alleles
(NCCCTS, 1981-2009). Clin Infect Dis. 2012;54:1595-605).
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.
Studies of T. gondii Antibodies in Schizophrenia
of antibodies in individuals who have schizophrenia
studies provide among the strongest evidence linking T. gondii to schizophrenia. This is in spite of the
fact that the standard assays currently in use to measure T. gondii antibodies are far
from perfect. Studies in our laboratory have suggested that the standard assays
may miss many Toxoplasma-infected
cases i.e., that many cases that are reported as negative are really positive
if a more sensitive assay was available.
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.
original study, there have been at least 70 additional studies. A 2007 review
of 42 of these studies included a meta-analysis of 23 of them in which the odds
ratio of having T. gondii antibodies with a diagnosis of schizophrenia
was OR 2.73. In other words, if a person has been infected with T. gondii, he/she has a 2.7 times
greater chance of having schizophrenia than if the person had not been infected
(Torrey EF, Bartko JJ, Lun Z-R, et al. Antibodies to Toxoplasma gondii in
patients with schizophrenia: a meta-analysis. Schizophr Bull. 2007;33:729–736).
A 2012 updated
meta-analysis of 38 such studies included 6,067 individuals with schizophrenia
and 8,715 controls. The meta-analysis also reported an odds ratio of OR 2.71 (1.93–3.80)
(Torrey EF, Bartko JJ, Yolken RH. Toxoplasma
gondii : meta-analysis and assessment as a risk factor for schizophrenia.
Schizophr Bull. 2012;38:642-647). These studies were done in 14 different
countries; thus, the finding of increased antibodies against T. gondii in individuals with schizophrenia has been
remarkably consistent geographically and over half a century.
There is some clear
evidence from these antibody studies that the increase in antibodies is not
secondary to antipsychotic medication. The study by Leweke et al. in Germany
assessed antibodies to T. gondii in 36 individuals with schizophrenia who had
never been treated, 10 who had had past treatment, and 39 receiving current
treatment. The level of both serum and CSF antibodies to T. gondii was highest in the
never-treated patients, intermediate in those treated in the past, and lowest
in those receiving current treatment (Leweke FM, Gerth CW, Koethe D, et al.
Antibodies to infectious agents in individuals with recent onset schizophrenia.
Eur Arch Psychiatry Clin Neurosci. 2004;254:4–8).
of antibodies in individuals prior to the onset of schizophrenia
In a study of
military personnel, serum specimens were available from periods of up to 11
years prior to the onset of schizophrenia. The serum of 180 individuals with
schizophrenia and 532 matched (3:1) controls were assessed for IgG antibodies
to T. gondii and other infectious agents. Among those with
schizophrenia, significantly increased levels of antibodies were seen prior to
the onset of illness (hazard ratio = 1.24, p<0.01), maximal in the 6 months
prior to onset but seen as early as 3 years prior to the onset (Niebuhr DW,
Millikan AM, Cowan DN, et al. Selected infectious agents and risk of
schizophrenia among U.S. military personnel. Am J Psychiatry. 2008;165:99–106).
An attempt was made to replicate this finding, using the same methodology, in a
larger military cohort of 855 individuals with schizophrenia and 1,165
controls. The results failed to replicate the original finding (hazard ratio –
1.06, p=0.27) (Li Y, Weber NS, Fisher JA, et al. Association between antibodies
to multiple infectious and food antigens and new onset schizophrenia among US
military personnel. Schizophr Res. 2013;151:36-42).
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).
of antibodies in individuals prior to the onset of schizophrenia was carried
out in Denmark using their national case register. Among 45,609 women who gave
birth between 1992 and 1995 (at which time T.
gondii antibodies were assessed), 80
developed schizophrenia during the following 13–16 years, indicating a relative
risk of 1.68 (0.77–3.46). “When the mothers were classified according to IgG
level, only those with the highest IgG levels had a significantly higher risk
of schizophrenia spectrum disorder” (Pedersen MG, Stevens H, Pedersen CB, et
al. Toxoplasma infection and later
development of schizophrenia in mothers. Am J Psychiatry. 2011;168:814-821).
A study in
Wuhan, China, assessed antibodies to T.
gondii in 7,126 students entering
Wuhan University for their first year. At the time of entering the university,
707 (9.9%) had IgG and 113 (1.6%) had IgM antibodies to T. gondii. The students were then followed for the next four years
and all those who developed a psychotic disorder were noted. At the end of that
time, 84 students (1.2%) had developed a psychotic disorder. Among those with
psychosis, 18 (21.4%) had IgG antibodies and 9 (10.7%) had IgM antibodies to T. gondii at the time they entered the university.
Regarding T. gondii as a risk factor for psychosis, 18 of the 707
(2.6%) students with IgG antibodies developed psychosis compared to 66 of the
6,419 (1.0%) students without IgG antibodies. Similarly, 9 of the 113 (8.0%)
students with IgM antibodies developed psychosis compared to 104 of the 7,013
(1.5%) students without IgM antibodies (unpublished study).
of antibodies in newborn children who later develop schizophrenia
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
Blomstrom et al. examined sera (filter paper samples) collected at birth in
1975-1985 on 198 individuals who were later diagnosed with schizophrenia and
524 matched controls. Levels of IgG antibodies to T. gondii at birth were
associated with the subsequent diagnosis of schizophrenia (OR=2.1, 95%CI
1.0-4.5) (Blomström A, Karlsson H, Wicks S, Yang S, Yolken RH, Dalman C. Maternal
antibodies to infectious agents and risk for non-affective psychoses in the
offspring--a matched case-control study. Schizophr Res. 2012;140:25-30).
of antibodies in maternal sera from late in pregnancy
Brown et al.
assessed antibodies to T. gondii in 63 women who gave birth to individuals
(cases) who later developed schizophrenia, schizoaffective disorder, or
schizophrenia spectrum disorders. They used 123 matched controls. Among the
cases, the incidence of high IgG antibody titres was significantly increased
(p=0.051; OR 2.61) (Brown AS, Schaefer CA, Quesenberry CP, et al. Maternal
exposure to toxoplasmosis and risk of schizophrenia in adult offspring. Am J
increased antibodies to T. gondii found in other psychiatric and/or
that increased antibodies to T. gondii are not specific to schizophrenia. A study of
199 patients with bipolar disorder reported an increased prevalence compared to
controls (Fekadu A, Shibre T, Cleare AJ. Toxoplasmosis as a cause for behaviour
disorders—overview of evidence and mechanisms. Folia Parasitol.
2010;57:105–113). This finding was subsequently replicated in a smaller American
sample (n=41) (Pearce BD, Kruszon-Moran D, Jones JL. The relationship between Toxoplasma gondii infection and mood disorders in the third National
Health and Nutrition survey. Biol Psychiatry. 2012;72:290-295). It was also
replicated in a French sample of 110 bipolar disorder patients and 106 healthy
controls (OR=2.2, p=0.028) (Hamdani N, Daban-Huard C, Lajnef M, et al. Relationship
between Toxoplasma gondii infection and bipolar disorder in a French
sample. J Affect Disord. 2013;148:444-8). Yet another study from Brazil
reported a significant increase in T.
gondii seropositivity in a small
sample of patients with mood disorder (n=28, including 24 bipolar and 14 major
depression) compared to healthy controls (n=95) (Nascimento FS, de Rosalmeida
Dantas C, Netto MP, et al. Prevalence of antibodies to Toxoplasma gondii in
patients with schizophrenia and mood disorders. Schizophr Res. 2012;142:244-5).
A study of 42
patients with obsessive-compulsive disorder also reported an increased
prevalence of antibodies to T. gondii compared to controls (Miman O, Mutlu EA, Ozcan
O, et al. Is there any role of Toxoplasma
gondii in the etiology of
obsessive-compulsive disorder? Psychiatry Res. 2010;177:263–265). Similarly, a
study of a large community cohort in Detroit reported that T. gondii seropositivity was
associated with a diagnosis of general anxiety disorder but not with PTSD or
depression (Markovitz et al, submitted). Another study of 414 pregnant women reported that the
44 women with antibodies to T. gondii were more likely to be depressed and anxious
(Groër MW, Yolken RH, Beckstead JW, et al. Prenatal depression and anxiety in Toxoplasma gondii positive women. Am J Obstet Gynecol.
One study of
patients with Parkinson’s disease reported an increase in T. gondii antibodies (Miman
O, Kusbeci OY, Aktepe OC, et al. The probable relation between Toxoplasma gondii and Parkinson’s disease. Neurosci Lett.
2010;475:129–131), but another study did not (Celik T, Kamisli O, Babur C, et
al. Is there a relationship between Toxoplasma
gondii infection and idiopathic
Parkinson’s disease? Scand J Infect Dis. 2010;42:604–608). Still other
neurological studies have linked T.
gondii antibodies to migraine
(Koseoglu E, Yazar S, Koc I. Is Toxoplasma
gondii a causal agent in migraine?
Am J Med Sci. 2009;338:120–122) and possibly to cryptogenic epilepsy (Stommel
EW, Seguin R, Thadani VM, et al. Cryptogenic epilepsy: an infectious etiology?
Epilepsia. 2011;42:436–438). A small study of Alzheimer’s disease reported a
significantly higher seropositivity for T.
gondii among patients than controls
(Kusbeci OY, Miman O, Yaman M, Aktepe OC, Yazar S. Could Toxoplasma gondii have any
role in Alzheimer disease? Alzheimer Dis Assoc Disord. 2011;25:1-3). Finally,
studies of brain cancers have suggested an association between the prevalence
rate of such cancers and prevalence of T.
gondii (Vittecoq M, Elguero E,
Lafferty KD, et al. Brain cancer mortality rates increase with Toxoplasma gondii seroprevalence in France. Infect Genet Evol.
2012;12:496-8; Ryan P, Hurley SF, Johnson AM, et al. Tumours of the brain and
presence of antibodies to Toxoplasma
gondii. Int J Epidemiol. 1993;22:412-9).
increased antibodies to T. gondii found in other non-psychiatric,
prevalence of antibodies to T. gondii has been reported in several other conditions.
One study, for example, reported that “individuals with positive T. gondii serology had twice the odds of being obese
compared to seronegative individuals (p=0.01) (Reeves GM, Mazaheri S, Snitker S,
et al. A positive association between T.
gondii seropositivity and obesity. Front
Public Health. 2013;1:73).
most interesting association of T. gondii
with other diseases is with
rheumatoid arthritis. Four studies have reported an increased prevalence of T. gondii antibodies in individuals with this disease (Tomairek
HA, Saeid MS, Morsy TA, Michael SA. Toxoplasma
gondii as a cause of rheumatoid
arthritis. J Egypt Soc Parasitol. 1982;12:17-23; Mousa MA, Soliman HE, el
Shafie MS, Abdel-Baky MS, Aly MM. Toxoplasma
seropositivity in patients with rheumatoid arthritis. J Egypt Soc Parasitol.
1988;18:345-51; Shapira Y, Agmon-Levin N, Selmi C, et al. Prevalence of anti-toxoplasma
antibodies in patients with autoimmune diseases.J Autoimmun. 2012;39:112-6; Fischer
S, Agmon-Levin N, Shapira Y, et al. Toxoplasma
gondii : bystander or cofactor in rheumatoid arthritis. Immunol Res.
2013;56:287-92). Another study reported that individuals with rheumatoid
arthristis compared to controls have had more exposure to cats (Gottlieb NL,
Ditchek N, Poiley J, Kiem IM. Pets and rheumatoid arthritis. An epidemiologic
survey. Arthritis Rheum. 1974;17:229-34). This association is especially
interesting because rheumatoid arthritis and schizophrenia share many
epidemiological features and it has been noted in many studies that the two
diseases are mutually exclusive, i.e., once you get either rheumatoid arthritis
or schizophrenia, you almost never get the other (Torrey EF, Yolken RH. The
schizophrenia-rheumatoid arthritis connection: infectious, immune, or both? Brain
Behav Immun. 2001;15:401-10). This suggests that T. gondii or another
pathogen may cause both diseases with the clinical outcome differing because of
genetic predisposition, timing of the initial infection, strain difference, or
antibodies to T. gondii remain detectable over many years?
It has been
widely assumed that once a person is exposed to T. gondii they will remain
antibody-positive for life. However, no long-term study has been done on this
question in humans. In 1941, Dr. Albert Sabin reported that in his experiments
on monkeys, “it has been observed that convalescent monkeys may lose their
antibodies as early as six weeks after infection” (Sabin AB. Toxoplasmic
encephalitis in children. JAMA. 1941;116:801–807). There are also suggestions
from human studies that seropositivity is not lifelong; in one study, the mean
duration of seropositivity was 40 years (Van Druten H, Van Knapen F, Reintjes
A. Epidemiologic implications of limited-duration seropositivity after Toxoplasma infection. Am J Epidemiol.
1990;132:169–180). There are at least two other studies of adult toxoplasmosis
reporting conversions from T. gondii seropositivity to seronegativity (van der Veen
J, Polak MF. Prevalence of Toxoplasma
antibodies according to age with comments on the risk of prenatal infection. J
Hyg (Camb). 1980;85:165–174; Konishi E. Annual change in immunoglobulin G and M
antibody levels to Toxoplasma gondii in human sera. Microbiol Immunol.
1989;33:403–411) and one study showing a similar change in cases of congenital
toxoplasmosis (Koppe JC, Kloosterman GJ. Congenital toxoplasmosis: long-term
follow-up. Paediatrie und Paedologie. 1982;17:171–179). Serial antibody studies
from our own laboratory also have recorded numerous individuals whose T. gondii antibody status has switched from positive to
negative over time.
VI. Neurotransmitters and T. gondii
For more than 40 years, it has been
known that neurotransmitters are involved in the pathogenesis of schizophrenia.
An excess of dopamine has been widely suspected, and along with genetics,
dopamine-excess has been one of the most thoroughly researched theories. Despite
hundreds of research projects, however, relatively few abnormalities in the
dopamine system have ever been identified in individuals with schizophrenia. In
recent years, more research attention has been focused on other
neurotransmitters, especially glutamate and GABA.
of interest in dopamine and T.
The origin of
interest in dopamine and T. gondii appears to have been the 1985 paper by Henry
H. Stibbs, Ph.D., then in the School of Public Health and Community Medicine at
the University of Washington. Stibbs had been studying trypanosomes and
sleeping sickness for 10 years and discovered that this organism increased
dopamine level by 34 percent in infected rats (Stibbs HH. Neurochemical and
activity changes in rats infected with Trypanosoma brucei gambiense. J
Parasitology. 1984;70:428–432). He therefore turned his attention to T. gondii because of its known ability to alter
learning, memory, and behavior in infected mice and rats. He infected 30 mice
with the C56 strain of T. gondii. Ten
mice were infected, became symptomatic, and were killed at 12 days (= acute
group). Ten mice were infected, treated with sulfadiazine, did not develop
symptoms, and were killed at 5 weeks (= chronic group). Ten control mice were
also killed at 5 weeks. The brains were assessed neurochemically and compared
to the controls. There were no changes in serotonin or 5-HIAA. Norepinephrine
was 28 percent decreased in acute but not in chronic infection. Homovanillic
acid (HVA) was 40 percent increased in acute but not chronic infection.
Dopamine was normal in acute infection but 14 percent increased in the treated
mice with chronic infection. Stibbs concluded that T. gondii causes
abnormalities in catecholamine metabolism and that these “may be factors
contributing to the psychological and motor changes” seen in experimentally
infected rodents (Stibbs HH. Changes in brain concentrations of catecholamines
and indoleamines in Toxoplasma gondii infected mice. Ann Trop Med Parasitol.
1985;79:153–157, copyright 1985, Maney Publishing,
www.maney.co.uk/journals/atmp; linked to PDF file with permission).
- Toxoplasma gondii has the ability to make dopamine
In 2009, Dr.
Glenn McConkey and his colleagues at the University of Leeds in the UK
demonstrated that T. gondii has the genes encoding two critical enzymes
needed to make dopamine. It has the gene for phenylalananine hydroxylase, which
changes phenylalanine to tyrosine, and also the gene for tyrosine hydroxylase,
which changes tyrosine to dopa, the precursor of dopamine. These genes were not
found in any other closely related parasites except Neospora. McConkey et al. subsequently confirmed that T. gondii does actually make dopamine and showed “a
direct correlation between the number of infected cells and the quantity of
dopamine released (Prandovszky E, Gaskell E, Martin H, et al. The neurotropic
parasite Toxoplasma gondii increases dopamine metabolism. PLoS One.
2011;6:e23866). This finding suggests the possibility that the excess dopamine
thought to occur in individuals with schizophrenia might be being introduced by
T. gondii rather than made by the affected individuals
(Gaskell EA, Smith JE, Pinney JW, et al. A unique dual activity amino acid
hydroxylase in Toxoplasma gondii.
PLoS One. 2009;4:e4801).
of changing levels of dopamine on behavior induced by
T. gondii infection
(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).
(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.
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 cell
cultures in our laboratory have shown a differential effect of different
strains on neurotransmitter-related gene expression (Xiao J, Li Y, Jones-Brando
L, Yolken RH. Abnormalities of neurotransmitter and neuropeptide systems in
human neuroepithelioma cells infected by three Toxoplasma strains. J Neural Transm. 2013;120:1631-9). Toxoplasma infection also has effects on
the expression of a number of other genes in neural cell cultures and in
experimentally infected mice.
of T. gondii infection on GABA
In addition to
affecting dopamine, it is now clear that T.
gondii may also affect the GABA
neurotransmitter system. GABA is the principal inhibitory neurotransmitter in
the brain and is known to be affected in schizophrenia. In 2012, Fuks et al. in
Sweden published a study showing that in mice T. gondii enters the brain
and induces an increased production of GABA (Fuks JM, Arrighi RB, Weidner JM, et
al. GABAergic signaling is linked to a hypermigratory phenotype in dendritic
cells infected by Toxoplasma gondii. PLoS
VII. Neuropathology of T. gondii
The neuropathology of schizophrenia
is subtle, with mild atrophy and dilated ventricles. The brain regions of
greatest interest have been the prefrontal cortex, hippocampus, and association
cortex, which includes the superior temporal gyrus and inferior parietal
lobule; other areas, such as the cingulate, basal ganglia, thalamus, and
cerebellum, are also thought to be involved. Abnormalities have been described
in both neurons and glia.
The neuropathology of congenital
toxoplasmosis has been well described. It consists of periaqueductal and
periventricular vasculitis with necrosis. Obstruction of the aqueduct may
produce hydrocephalis and the necrotic tissue may calcify (Frenkel JK. Pathology
and pathogenesis of congenital toxoplasmosis. Bull NY Acad Med.
The neuropathology of T. gondii infection acquired after birth has been less
completely described except for cases of immunosuppression, such as AIDS. In
one of the few cases reported, a 6-year-old boy died from acute Toxoplasma encephalitis and was
autopsied one hour after death. According to the report, “there was no gross
pathologic change . . . [and] the paucity of microscopic abnormalities was
equally surprising.” The author concluded: “It is also remarkable how the
observations in this case differ from the extensive, gross and microscopic
changes which have been observed in the one proved case of ‘congenital’
encephalitis due to Toxoplasma (Sabin
AB. Toxoplasmic encephalitis in children. JAMA. 1941;116:801–807). Other case reports
have also noted the paucity of CNS findings in adult toxoplasmosis; however,
one study reported widespread pathological findings in other organs, including
the liver and spleen (Callahan WP, Russell WO, Smith MG, Human toxoplasmosis: a
clinicopathologic study with presentation of five cases and review of the
literature. Medicine. 1946;25:343–397). There are scattered case reports of CNS
pathology in adult toxoplasmosis in immunocompetent hosts, such as
meningoencephalitis (Kaushik RM, Mahajan SK, Sharma A, et al. Toxoplasmic
meningoencephalitis in an immunocompetent host. Trans R Soc Trop Med Hyg.
2005;99:874–878) and brain abscess (Silva LA, Vieira RS, Serafini LN, et al.
[Toxoplasmosis of the central nervous system in a patient without immunosuppression:
case report]. Rev Soc Bras Med Trop. 2001;34:487–490); however, such reports
appear to be rare.
T. gondii is known to be highly neurotropic and to
infect both neurons and astrocytes (Halonen SK, Lyman WD, Chiu FC. Growth and
development of Toxoplasma gondii in human neurons and astrocytes. J Neuropath
Exp Neurol. 1996;55:1150–1156; Cruzet C, Robert F, Roisin MP, et al. Neurons in
primary culture are less efficiently infected by Toxoplasma gondii than glial
cells. Parasitol Res. 1998;84:25–30). In non-immunosuppressed individuals who
are diagnosed with acute toxoplasmic encephalitis, the CSF shows moderately
elevated protein, normal glucose levels, and T. gondii “is rarely
isolated from the CSF.” Necrosis and an intense inflammatory reaction are seen
on autopsy (Post MJD, Chan JC, Hensley GT. Toxoplasma
encephalitis in Haitian adults with acquired immunodeficiency syndrome: a
clinical-pathologic-CT correlation. Am J Roentgenol. 1983;140:861–868). In
immunosuppressed individuals, T. gondii may cause an acute necrotizing encephalitis
that is most severe in the frontal and parietal lobes, basal ganglia, and
thalamus (Shankar SK, Mahadevan A, Satishchandra P, et al. Neuropathology of
HIV/AIDS with an overview of the Indian scene. Indian J Med Res. 2005;121:468–488;
Dellacasa-Lindberg I, Hitziger N, Barragan A. Localized recrudescence of Toxoplasma infections in the central
nervous system of immunocompromised mice assessed by in vivo bioluminescence
imaging. Microbes Infect. 2007;9:1291–1298).
Less information is available on the
neuropathology of individuals chronically infected with T. gondii with bradyzoites.
A study of 46 postmortem cases of AIDS patients with T. gondii infection reported
“one case with intact tissue cysts in the parietal white matter as the only
histopathologically identifiable lesion” (Strittmatter C, Lang W, Wiestler OD,
et al. The changing pattern of human immunodeficiency virus-associated cerebral
toxoplasmosis: a study of 46 postmortem cases. Acta Neuropathol.
studies of T. gondii in schizophrenia
In an MRI
study of 44 individuals with schizophrenia, it was shown that patients who were
seropositive for T. gondii antibodies had more gray matter reduction than
patients who were seronegative (Horacek J, Fleger J, Tintera J, et al. Latent
toxoplasmosis reduces gray matter density in schizophrenia but not in controls:
Voxel –based-morphometry (VBM) study. World J Biol Psychiatry. 2012;13:501-509).
Two histological studies have been done. Conejero-Goldberg studied the orbital
frontal cortex of postmortem specimens from 14 individuals with schizophrenia,
11 with other psychiatric diagnoses, and 26 normal controls. The primers “were
designed to amplify a conserved region in the parasitic genome and a fragment
of the hsp/Bag1gene (a bradyzoite-expressed gene)” using a nested polymerase
chain reaction. All specimens were negative (Conejero-Goldberg C, Torrey EF,
Yolken RH. Herpesviruses and Toxoplasma
gondii in orbital frontal cortex of
psychiatric patients. Schizophr Res. 2003;60:65–69). In another study, S.K.
Halonen et al. used RT-PCR to look for evidence of T. gondii in the brain
(frontal, parietal and temporal samples) of an individual with schizophrenia
who was seropositive; no evidence of T.
gondii was found (Halonen, SK. Final
report, Schizophrenia and Toxoplasma
gondii pilot project. Stanley
Medical Research Institute. June 2011).
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
In addition to
neuropathological studies, it is also possible to identify the presence of T. gondii in brain tissue by inoculating the brain
tissue into mice known to be uninfected and then looking for evidence of
infection. A 1965 study that did this with brain autopsy tissue from 44
individuals known to have serological antibodies to T. gondii reported that the
mice became antibody-positive in 4 of the 44 cases. In other cases, in addition
to the 44, the mice became antibody-positive after being injected with muscle
tissue (Remington JS, Cavanaugh AB. Isolation of the encysted form of Toxoplasma gondii from human skeletal muscle and brain. N Engl J
VIII. Treatment Approaches to
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).
report of antipsychotic inhibition of Toxoplasma
gondii was an in vitro study using
the phenothiazine trifluoperazine (Stelazine), which was said to have
“membrane-active detergent-like effects” on T.
gondii (Pezzella N, Bouchot A,
Bonhomme A, et al. Involvement of calcium and calmodulin in Toxoplasma gondii tachyzoite invasion. Eur J Cell Biol.
1997;74:92–101). An extensive in vitro study of eight antipsychotics and
metabolites and four mood stabilizers compared their effectiveness in
inhibiting T. gondii against the effectiveness of trimethroprim, a
standard treatment for toxoplasmosis. Haloperidol was more effective than
trimethoprim. Valproic acid and sodium valproate were equally effective to
trimethoprim. Chlorpromazine, fluphenazine, risperidone, clozapine, quetiapine,
and carbamazapine all showed some activity but less than trimethoprim. Lithium
showed no inhibition of T. gondii (Jones-Brando L, Torrey EF, Yolken R. Drugs
used in the treatment of schizophrenia and bipolar disorder inhibit the
replication of Toxoplasma gondii.
Schizophr Res. 2003;62:237–244). A partial replication of this study was
carried out using some different methods and assays. In this study,
haloperidol, clozapine and valproic acid had no measurable effect but
fluphenazine, thioridazine and trifluoperazine did (Goodwin DG, Strobl J,
Mitchell SM, Zajac AM, Lindsay DS. Evaluation of the mood-stabilizing agent
valproic acid as a preventative for Toxoplasmosis in mice and activity against
tissue cysts in mice. J Parasitol. 2008;94:555-557; Goodwin DG, Strobl JS,
Lindsay DS. Evaluation of five antischizophrenic agents against Toxoplasma gondii in human cell cultures. J Parasitol.
2011;97:148-151). In another replication of this study fluphenazine and
zuclopenthixol showed good inhibition of T.
gondii; haloperidol, levomepromazine and loxapine showed fair inhibition; and
amisulpride, risperidone and valproic acid showed poor inhibition (Fond G,
Macgregor A, Tamouza R, et al. Comparative analysis of anti-toxoplasmic
activity of antipsychotic drugs and valproate. Eur Arch Psychiatry Clin
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 azithromycin
in individuals with schizophrenia who are seropositive for Toxoplasma gondii. Schizophr Bull. 2007;112:198–199).
• Trimethoprim 200 mg: 91 male outpatients with mostly chronic schizophrenia;
double-blind, placebo trial; 6 months; add-on to chlorpromazine or haloperidol.
Both groups improved markedly, perhaps reflecting being on a regular
antipsychotic with monitoring and follow-up. The trimethoprim group improved
more on the negative symptom subscale, but the difference did not achieve
statistical significance (Shibre T, Alem A, Abdulahi A, et al. Trimethoprim as
adjuvant treatment in schizophrenia: a double-blind, randomized,
placebo-controlled clinical trial. Schizophr Bull. 2010;36:846–851).
• Artemisinin: an anti-malarial, was given 200 mg/d or placebo to 66
outpatients with schizophrenia for 10 weeks. There was no significant
difference in positive or negative symptoms between groups. However, the
artemisinin significantly decreased the level of antibodies to gliadin
(p<0.0005) (Dickerson F, Stallings C, Vaughan C, et al. Artemisinin reduces
the level of antibodies to gliadin in schizophrenia. Schizophr Res. 2011;129:196–200).
• Artemether: an anti-malarial related to artemisinin, or placebo was
given for 8 weeks to 100 individuals with first-episode schizophrenia, all
positive for antibodies to T. gondii, in a double-blind study. They were all
also taking risperidone. On the PANSS scale for negative symptoms, but not
other scales, the patients on artemether improved significantly more than
controls (p<0.05) (Wang H, Li Q, Wang X, et al. Clinical trial of artemether
in schizophrenia patients with seropositivity to Toxoplasma gondii. J Psych Res. In press).
limiting factor in treating humans infected with T. gondii is that so far no
drug has ever been shown to be effective against the cyst stage of the
organism, sequestered in the person’s muscles and brain. Research carried out
by our colleagues has recently identified promising candidates which are under investigation.
These include a derivative of quinolone drugs, widely used to treat malaria,
which appears to be effective in inhibiting the toxoplasmosis brain cysts;
these drugs are being developed in the laboratory of Mike Riscoe at the
University of Oregon.
of drug being developed for possible use in treating T. gondii brain infections
are analogues of sphingosine, a brain lipid similar to one derived from wild cherry.
These are being developed in the laboratory of James McNulty at McMaster
University in Ontario (McNulty J, Vemula R, Bordon C, et al. Synthesis and
anti-toxoplasmosis activity of 4-arylquinoline-2-carboxylate derivatives. Org
Biomol Chem. 2014;12:255-60). One drug in this group, fingolimod, is currently
available for the treatment of multiple sclerosis and is undergoing a treatment
trial to assess its efficacy in individuals with schizophrenia. Artemisinin
derivatives which reduce the burden of T.
gondii brain cysts are also being
developed in the laboratory of Vern Carruthers at the University of Michigan (Schultz
TL, Hencken CP, Woodard LE, et al. A thiazole derivative of artemisinin
moderately reduces Toxoplasma gondii cyst burden in infected mice. J Parasitol.