Toxoplasma gondii and Schizophrenia

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http://www.cdc.gov/ncidod/EID/vol9no11/03-0143.htm

 

 

Toxoplasma gondii and Schizophrenia

 

E. Fuller Torrey* and Robert H. Yolken†

*Stanley Medical Research Institute, Bethesda, Maryland, USA; and

†Johns Hopkins University Medical Center, Baltimore, Maryland, USA

 

Suggested citation for this article: Torrey EF, Yolken RH.

Toxoplasma gondii and schizophrenia. Emerg Infect Dis [serial online]

Nov 2003 [date cited]. Available from: URL:

http://www.cdc.gov/ncidod/EID/vol9no11/03-0143.htm

 

Recent epidemiologic studies indicate that infectious agents may

contribute to some cases of schizophrenia. In animals, infection with

Toxoplasma gondii can alter behavior and neurotransmitter function. In

humans, acute infection with T. gondii can produce psychotic symptoms

similar to those displayed by persons with schizophrenia. Since 1953,

a total of 19 studies of T. gondii antibodies in persons with

schizophrenia and other severe psychiatric disorders and in controls

have been reported; 18 reported a higher percentage of antibodies in

the affected persons; in 11 studies the difference was statistically

significant. Two other studies found that exposure to cats in

childhood was a risk factor for the development of schizophrenia. Some

medications used to treat schizophrenia inhibit the replication of T.

gondii in cell culture. Establishing the role of T. gondii in the

etiopathogenesis of schizophrenia might lead to new medications for

its prevention and treatment.

 

Schizophrenia is a pervasive neuropsychiatric disease of uncertain

cause that affects approximately 1% of the adult population in the

United States and Europe. An increased occurrence of schizophrenia in

family members of affected persons suggests that genetic factors play

a role in its etiology, and some candidate predisposing genes have

been identified. Environmental factors are also important.

Epidemiologic studies, for example, have established that

winter-spring birth, urban birth, and perinatal and postnatal

infection are all risk factors for the disease developing in later

life. These studies have rekindled an interest in the role of

infectious agents in schizophrenia, a concept first proposed in 1896

(1). This review focuses on evidence specifically linking infection

with Toxoplasma gondii to the etiology of some cases of schizophrenia.

 

T. gondii is an intracellular parasite in the phylum Apicomplexa. Its

life cycle can be completed only in cats and other felids, which are

the definitive hosts. However, T. gondii also infects a wide variety

of intermediate hosts, including humans. In many mammals, T. gondii is

known to be an important cause of abortions and stillbirths and to

selectively infect muscle and brain tissue. A variety of neurologic

symptoms, including incoordination, tremors, head-shaking, and

seizures, have been described in sheep, pigs, cattle, rabbits, and

monkeys infected with T. gondii (2).

 

Humans may become infected by contact with cat feces or by eating

undercooked meat. The importance of these modes of transmission may

vary in different populations (3). Individual response to Toxoplasma

infection is determined by immune status, timing of infection, and the

genetic composition of the host and the organism (4).

 

Toxoplasma organisms have also been shown to impair learning and

memory in mice (5) and to produce behavioral changes in both mice and

rats. Of special interest are studies showing that Toxoplasma-infected

rats become less neophobic, leading to the diminution of their natural

aversion to the odor of cats (6). These behavioral changes increase

the chances that the rat will be eaten by a cat, thus enabling

Toxoplasma to complete its life cycle, an example of evolutionarily

driven manipulation of host behavior by the parasite.

 

In humans, Toxoplasma is an important cause of abortions and

stillbirths after primary infection in pregnant women. The organism

can also cross the placenta and infect the fetus. The symptoms of

congenital toxoplasmosis include abnormal changes in head size

(hydrocephaly or microcephaly), intracranial calcifications, deafness,

seizures, cerebral palsy, damage to the retina, and mental

retardation. Some sequelae of congenital toxoplasmosis are not

apparent at birth and may not become apparent until the second or

third decade of life. Hydrocephalus (7), increased ventricular size

(8), and cognitive impairment (9) have also been noted in some persons

with schizophrenia and other forms of psychosis.

 

Some cases of acute toxoplasmosis in adults are associated with

psychiatric symptoms such as delusions and hallucinations. A review of

114 cases of acquired toxoplasmosis noted that " psychiatric

disturbances were very frequent " in 24 of the case-patients (10). Case

reports describe a 22-year-old woman who exhibited paranoid and

bizarre delusions ( " she said she had no veins in her arms and legs " ),

disorganized speech, and flattened affect; a 32-year-old woman who had

auditory and visual hallucinations; and a 34-year-old woman who

experienced auditory hallucinations and a thought disorder (11).

Schizophrenia was first diagnosed in all three patients, but later

neurologic symptoms developed, which led to the correct diagnosis of

Toxoplasma encephalitis.

 

Psychiatric manifestations of T. gondii are also prominent in

immunocompromised persons with AIDS in whom latent infections have

become reactivated. Reviews of such AIDS cases with toxoplasmosis have

indicated that altered mental status may occur in as many as 60% of

patients and that the symptoms may include delusions, auditory

hallucinations, and thought disorders (12).

 

Additional studies have documented that persons with serologic

evidence of Toxoplasma infection have evidence of psychiatric changes

in the absence of a history of clinically apparent Toxoplasma

infection. Studies in which personality questionnaires have been

administered to healthy adults have indicated that serum antibodies to

T. gondii are associated with alterations in behavior and psychomotor

skills (13). Seropositivity to Toxoplasma has also been associated

with " lack of energy or tiredness " in schoolchildren (14). In view of

these findings, we decided to carry out serologic and other studies

and to survey the literature for possible additional links between

Toxoplasma infection and schizophrenia.

Serologic Studies of Patients with Schizophrenia

Studies Before 1980

 

In the course of doing our studies, we discovered that much research

had been published in languages other than English and was not listed

on searchable databases. Through direct contact with authors and by

obtaining references listed on their papers, we identified 13 relevant

studies published between 1953 and 1979 (15–27), as listed on the

Table. Some publication bias is likely, since negative studies are

less likely to have been submitted or published.

 

The 13 studies used a variety of immunologic methods for measuring

antibodies, including the Sabin Feldman dye test, skin tests, and

complement fixation (CF). One study used a test in which an alkaloid

from T. gondii caused a tropical fish, Lebistes reticulatus, to change

color (19). Some of the studies compared the relative efficacy of two

different tests. Most of the studies defined Toxoplasma-positive

results as the presence of a skin reaction or antibodies above a

certain titer but often without specifying the precise details of the

method; thus, comparing the older studies with each other was not

possible. Most of these studies also did not specify what diagnostic

criteria were used for schizophrenia, but since at least 12 of them

used inpatients, the patients likely had a severe psychiatric

disorder. Similarly, most of the studies did not specify the origin of

their control group other than saying such things as " 681 healthy

persons working or studying in the city of Gdansk " (15).

 

Despite these limitations, 12 of the 13 studies found that the patient

group had a higher percentage of antibodies to Toxoplasma than the

control group. In eight of the studies, the increase was statistically

significant by chi square at the level of p < 0.05. In the two largest

studies, Kozar (15) in Poland reported antibodies in 495 (52%) of 961

psychiatric inpatients compared with 170 (25%) of 681 controls, and

Roch and Varela (25) in Mexico found antibodies in 836 (86%) of 973

patients with schizophrenia compared with finding antibodies in 30% of

the general population.

Studies Since 1999

 

We identified no studies that were done between 1979 and 1999. Since

that time, six studies have been carried out, including our own

(28–32). All used enzyme immunoassay methods for measuring antibodies

to Toxoplasma. All of the studies also used modern diagnostic criteria

for schizophrenia; three studies included patients with chronic

disease, and three included patients who were in the first episode of

the disease. All of the studies identified their control groups, and

some attempts were made to match them to the patient groups.

 

The results of these studies are summarized in the Table. In all of

the studies, the patients had more antibodies to Toxoplasma than the

control groups, and in the three studies, carried out in China and

Germany, of patients who were having their first-episode of

schizophrenia, the differences were statistically significant. One of

the first-episode studies, carried out in Cologne by Leweke et al.

(32), divided the first-episode patients into those who had never

received antipsychotic treatment and those who had received some

treatment. The antibody levels for the treated group were intermediate

between the levels of the never-treated group and those of the control

group, suggesting that antipsychotic medication may have decreased the

antibody levels. This conclusion is supported by a study that

indicated that some antipsychotic medications inhibit the growth of T.

gondii in cell culture (33).

 

The Leweke et al. study also collected cerebrospinal fluid (CSF) from

the first-episode patients. The level of Toxoplasma antibody in the

CSF of untreated patients was significantly higher than the normal

controls (p < 0.0001) (32). Treated first-episode patients had CSF

antibody levels intermediate between those of the untreated patients

and the controls, just as was found for the sera.

 

In addition to these studies on adults with schizophrenia, a study was

also conducted by analyzing serum samples from pregnant women,

obtained shortly before delivery, who gave birth to children in whom

schizophrenia or other psychoses developed. Preliminary analysis

indicates an increased rate of immunoglobulin (Ig) M (but not IgG)

class antibodies to Toxoplasma gondii in mothers with infants in whom

schizophrenia developed later, suggesting that the mothers were

experiencing an active infection or that they had persistent IgM

antibodies, as described in other studies. Increased levels of IgM

antibodies were not found to other perinatal pathogens such as rubella

virus or cytomegalovirus (34).

Discussion

 

Multiple studies have demonstrated that the brains of persons with

schizophrenia show structural and functional changes and that these

exist even in patients who have never been treated with antipsychotic

medications (35). Thus, schizophrenia, like multiple sclerosis and

Parkinson's disease, is a chronic disease of the central nervous

system; as with other such diseases, infectious agents should be

considered as possible etiologic agents, perhaps in persons who also

have an increased genetic susceptibility.

 

T. gondii is of special interest because of its known affinity for

brain tissue and its capacity for long-term infection starting in

early life. The effect of Toxoplasma infection on any given person may

differ, depending on such factors as individual genetic

predisposition, the state of the immune system, the dose, the

virulence of the infecting strain, the timing (e.g., infections in the

first trimester of pregnancy differ from those in the third trimester;

prenatal and postnatal infections differ; etc.), and the part of the

brain affected.

 

If Toxoplasma is involved in the etiology of schizophrenia, however,

its synergy with genes may determine the person's brain development,

immune response to infections, and response to other infectious

agents. The fact that T. gondii has been shown to activate

retroviruses in animal model systems may be relevant (36). This

property is consistent with the recent finding that many persons with

schizophrenia exhibit increased retroviral activation within their

central nervous systems (37).

 

Numerous studies indicate that, although the symptoms of schizophrenia

generally do not manifest until late adolescence or early adulthood,

the disease process has its origins in earlier stages of brain

development. The ability of Toxoplasma organisms to infect the

perinatal brain is thus consistent with this aspect of schizophrenia

pathogenesis. However, prospective studies also support a possible

role of postnatal infections in some cases of schizophrenia (38). The

potential effects of the transmission of Toxoplasma in early childhood

or later in life should thus be considered.

 

Epidemiologically, two studies have reported that adults who have

schizophrenia or bipolar disorder had a greater exposure to cats in

childhood. In one study, 84 (51%) of the 165 affected versus 65 (38%)

of the 165 matched controls had owned a house cat in childhood (p =

0.02) (39). In the other study, 136 (52%) of the 262 affected versus

219 (42%) of the 522 matched controls owned a cat between birth and

age 13 (odds ratio 1.53; p < 0.007) (40). Whether any geographic

association exists between the prevalence of toxoplasmosis and the

prevalence of schizophrenia is unknown. France, which has a high

prevalence of Toxoplasma-infected persons, was reported to have

first-admission rates for schizophrenia approximately 50% higher than

those in England (41). Ireland also has a high rate of

Toxoplasma-infected persons in rural areas (42), confirmed by the high

rate of infection in hospital personnel in our own study. The area of

our study in Ireland has also been reported to have a high prevalence

of schizophrenia (43).

 

Neuropathologically, studies of T. gondii in cell culture have shown

that glial cells, especially astrocytes, are selectively affected

(44,45). Postmortem studies of schizophrenic brains have also reported

many glial abnormalities (46), including decreased numbers of

astrocytes (47). Similarly, animal studies of Toxoplasma infections

have demonstrated that this organism affects levels of dopamine,

norepinephrine, and other neurotransmitters, which are well known to

be affected in persons with schizophrenia.

 

Few data exist concerning the clinical correlates of Toxoplasma

infection in persons with schizophrenia. A recent study found that

persons with schizophrenia who have serologic evidence of Toxoplasma

infection have increased levels of cognitive impairment compared to

age-matched Toxoplasma-seronegative patients with similar degrees of

psychotic symptoms (31). Additional studies are needed on the possible

associations between Toxoplasma infections and the symptoms or

clinical course of schizophrenia and other psychiatric diseases.

 

One limitation of studies of Toxoplasma infection and schizophrenia is

that one cannot conclusively rule out disease-related differential

exposure to the organism. Thus, hospitalized patients may be fed

undercooked meat, thereby increasing their seropositivity.

Alternatively, the authors of one of the studies speculated that the

increased patient seropositivity might have been because the patients

worked in the hospital gardens, which were also frequented by cats

(21). The possible effects of hospitalization, altered behavior, or

other artifactual factors on seropositivity can be minimized by the

analysis of persons with the recent onset of symptoms, as three

studies described above have done.

 

Studies are ongoing in attempts to better define the relationship of

Toxoplasma infection to schizophrenia. An initial study of the orbital

frontal cortex of 14 persons with schizophrenia (48), in which primers

to T. gondii were used, did not detect sequences. Studies should also

include organisms such as Neospora caninum and Hammondi hammondi,

which are closely related to T. gondii and which cross-react

serologically (49); N. caninum has been detected in human specimens in

our laboratory and by others (50). The use of organism-specific

antigens generated from molecular cloning and the use of

stage-specific antibodies should help elucidate both the specificity

and the timing of the infection.

 

Finally, clinical trials are under way of antimicrobial drugs with

anti-Toxoplasma activity, such as trimethoprim-sulfamethoxazole and

azithromycin, as adjunctive treatment for persons with schizophrenia

in double-blind trials. These studies may lead to new methods for the

treatment of schizophrenia and other psychiatric disorders that may be

associated with Toxoplasma and related organisms.

Acknowledgments

 

We gratefully acknowledge the following persons for allowing us to

use unpublished data: John Boronow, Faith Dickerson, Christoph Gerth,

Joachim Klosterkötter, Dagmar Koethe, Beth Lee, Markus Leweke, Andrea

Origoni, and Cassie Stallings.

 

Dr. Torrey is the associate director for laboratory research at

the Stanley Medical Research Institute and professor of psychiatry at

the Uniformed Services University of the Health Sciences, Bethesda,

MD. Dr. Yolken is the director of the Stanley Laboratory of

Developmental Neurovirology and the Stanley Distinguished Professor of

Pediatrics at Johns Hopkins University Medical Center, Baltimore, MD.

Their research focuses on the causes and treatment of schizophrenia

and bipolar disorder.

 

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