Toxoplasma gondii and Schizophrenia

E. Fuller Torrey, Robert H. Yolken

Disclosures

Emerging Infectious Diseases. 2003;9(11) 

In This Article

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.

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