Both studies found a modest association between IgG antibodies to T. gondii
and schizophrenia-related disorders. In the study of Brown et al, the results achieved statistical significance for the entire sample of schizophrenia-related diagnoses (OR 2.61; 1.00–6.82). The result for schizophrenia alone was not reported in that article. In the study by Mortensen et al,13
the association was significant for schizophrenia (OR 1.79; 1.01–3.15). The association with schizophrenia-related diagnoses and affective disorders, respectively, was much weaker and not close to being statistically significant.
No increase in IgM antibodies was found in either study, suggesting that there was no evidence of acute infection in either the mother or the child. Such acute infections are, of course, known to have deleterious effects, usually evident shortly after birth, including congenital malformations, retinal damage, cognitive deficits, etc. The study by Lebech et al,15
which screened 90 000 pregnant women and births for T. gondii
-specific IgG and IgM, reported that <1% of the cases had actually been exposed to an acute T. gondii
maternal infection in utero; so it is not surprising that no increase in IgM was found in these 2 studies. At present, therefore, the evidence suggests a linkage between maternal prevalence of past infection with T. gondii
and an increased risk of the development of schizophrenia in her offspring but not a direct effect of an acute maternal infection.
Causal mechanisms that could explain such an association are speculative. One possibility is a direct effect of the maternal IgG on the fetus, or an effect of a latent infection, because it is known that women with high IgG may have latent infections. If there is a direct effect of circulating anti-T. gondii
IgG, one could speculate that the pathogenic mechanism is similar to what is hypothesized to occur in some paraneoplastic CNS manifestations. Here symptoms, including psychiatric symptoms, are related to the levels of circulating tumor-specific antibodies, and a causal hypothesis is that the tumor expresses proteins that normally are expressed only in the brain and are recognized by the immune system as foreign when expressed outside the immunologically privileged brain.16
In addition, there is evidence that autoantibodies can affect cognition, emotion, and behavior and are crucial in the pathogenesis of CNS changes in systemic lupus erythematosus, partly due to the binding of antiantibodies to the N
-methyl-D-Aspartate (NMDA) receptor.17–19
This could, at least by analogy, suggest possible mechanisms through which anti-T. gondii
IgG could affect the brain in a way relevant to schizophrenia.
Another possible explanation is that the presence of maternal IgG reflects a lifestyle that increases the probability of the child being exposed to T. gondii after birth. For example, seropositive women may be more likely to have cooking practices that are conducive to food-borne infection with T. gondii, or more likely to expose her children to cats, the prime vector of the infection.
Another example of the effects of a maternal infection with an intracellular organism on the developing CNS of the offspring is cytomegalovirus (CMV). Infections with CMV in utero have been shown to reduce the expression of the NMDA receptor in the offspring of mice exposed to CMV through their mother20
; this receptor is known to be important in normal brain development, including development of the hippocampus.21
Similarly, infections in adult mice with T. gondii
can affect neurotransmission through increased levels of dopamine and homovanillic acid.22
One could speculate that similar neurotransmitter mechanisms may be operant, eg, through the reactivation of a maternal T. gondii
infection. It is also possible that maternal antibodies against T. gondii
are an indicator of increased infections with other organisms that spread through similar mechanisms, ie, as a zoonosis from cats or through undercooked meat.
Another possible mechanism through which exposure to infectious agents, including T. gondii
, could contribute to schizophrenia risk is through early sensitization of the immune system, as hypothesized by Müller and Schwarz.23
This might produce an imbalance of the immune response found in some patients with schizophrenia; this immune constellation, in turn, could lead to the accumulation of kynurenic acid in the CNS, which, due to its NMDA antagonistic properties and could lead to cognitive dysfunction and psychotic symptoms.
Although these explanations are at present speculative, the association between maternal antibodies against T. gondii
and schizophrenia is consistent with studies identifying T. gondii
as a plausible candidate organism to affect the brain. As reported elsewhere in this issue, many studies have found a higher frequency of T. gondii
antibodies in schizophrenia patients compared with controls; exposure was measured more directly than is sometimes the case when recording exposure in epidemiological studies of schizophrenia. In addition, studies have suggested that growing up in an environment with cats is associated with an increased risk of schizophrenia, suggesting a role for early infections.24
It is likely that an early infection with T. gondii
in itself may not be a sufficient cause of schizophrenia, but it may be one factor that interacts with a genetic predisposition to schizophrenia, possibly, acting at particularly vulnerable stages of neurodevelopment.
We are pursuing this research in an expanded study using the same Danish data sources as described in this review. The study, now in progress, includes more than 1300 individuals with schizophrenia. In this study, we are including risk genes for schizophrenia (and other relevant gene variants) and assessing the infection status in the neonatal samples by measuring specific IgG levels, mainly of maternal origin, and IgM, indicating that the newborn has been exposed to an infectious agent. We will also measure cytokines and other inflammatory markers; such markers can indicate both the response to an infection and exposure to hypoxia. These findings will be assessed in the context of other known risk factors for schizophrenia, which may provide valuable new insights into the etiology of this disease.
The task of identifying the causal pathways of schizophrenia will not be easy, however, even with the advantage of resources provided by large population-based registers and biobanks. If, eg, the timing of the infection is crucial, it may be difficult to obtain the most informative samples, which would include information and biological material from conception to the onset of disease. Despite the limited current empirical evidence identifying T. gondii as a risk factor for schizophrenia, we believe that it is a promising candidate and that its role as a risk factor and possible interaction with other risk factors warrants further study.