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Updated 22 February 2007 E-mail discussion
Printable version

Forum Discussion: Antibodies to Toxoplasma gondii in Patients with Schizophrenia: A Meta-Analysis


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In our Forum discussion “journal club” series, the editors of Schizophrenia Bulletin or Schizophrenia Research provide access to the full text of a recent article. A short introduction by a journal editor gets us started, and then it's up to our readers to share their ideas and insights, questions, and reactions to the selected paper. So read on…

Torrey EF, Bartko JJ, Lun ZR, Yolken RH. Antibodies to Toxoplasma gondii in Patients With Schizophrenia: A Meta-Analysis. Schizophr Bull. 2006 Nov 3.

View Comments By:
Chris Carter — Posted 12 March 2007
Fuller Torrey — Posted 13 March 2007
John McGrath — Posted 14 March 2007
Mary Reid — Posted 29 March 2007
Huan Ngo — Posted 9 April 2007
Fuller Torrey — Posted 11 April 2007
Mary Reid — Posted 14 April 2007
Carla Gallo — Posted 22 June 2007


Background Text
by Gunvant Thaker, Maryland Psychiatric Research Center, and Associate Editor, Schizophrenia Bulletin

In an upcoming issue of Schizophrenia Bulletin, Torrey, Bartko, Lun, and Yolken report results from a meta-analysis of studies examining association between antibodies to Toxoplasma gondii and schizophrenia. One of the unique aspects of the meta-analysis is that the authors include all available datasets, including many that were published in languages other than English. The analysis includes studies from 17 countries, many from Eastern Europe and China, and only six studies had been written in English. This attempt to include all available datasets is one of the methodological strengths of the meta-analysis carried out by Torrey and colleagues. The results suggest that schizophrenia patients are more than two times likely to have antibodies to T. gondii than the comparison subjects (odds ratio of 2.79). However, these studies are not informative about the timing of infection that contributed to the development of the disorder. Previous studies that noted associations between schizophrenia and other infections such as influenza suggested exposure during the prenatal period, usually at the beginning of the second trimester, being the critical time. Almost all of the studies reviewed by Torrey and colleagues examined antibodies to T. gondii in patients who already had developed the illness. Findings in the first episode cohorts are reassuring and suggest that the exposure likely occurred prior to the onset of the psychotic symptoms. Authors also cite publications that implicate maternal T. gondii infection in the etiology of schizophrenia. This raises the question whether the presence of antibodies in adults reflects prenatal infection, or whether postnatal infection with T. gondii is also a risk factor.

This is an interesting report identifying another environmental risk factor for schizophrenia with public health implications of reducing the risk. However, the meta-analysis also raises several questions. The evidence provided by meta-analysis is indirect, supporting an association but raising the question: Is it causal? Robert Schwarcz and Christopher Hunter speculate that the answer is yes, and in an accompanying "At Issue" piece provide a plausible causal pathway involving astrocyte-derived kynurenic acid. Schwarcz and Hunter review the recent literature that suggests that there is massive astrocyte activation and dramatic increase in the brain content of kynurenic acid in animals infected with T. gondii. Furthermore, data suggest that elevation of brain kynurenic acid levels play a role in the pathophysiology of schizophrenia. The same issue of Schizophrenia Bulletin includes findings from two new studies that further confirm a link between schizophrenia and T. gondii (Dickerson et al., 2007; Mortensen et al., 2007).

The next question is: when is the exposure critical in causing the harm? This is relevant for public health goals of reducing risk, as well as for therapeutic strategies in individual patients. If the prenatal period is the critical vulnerable time for the exposure to have any effect, then treatment against T. gondii in adulthood will be ineffective. What are the underlying mechanisms by which exposure to T. gondii leads to schizophrenia vulnerability, and how do these interact with other risk factors, including genetic factors? These are some of the questions that will need to be addressed, and hopefully will draw comments and discussion from other readers.


Comments on Online Discussion
Comment by:  Chris Carter
Submitted 10 March 2007 Posted 12 March 2007

Toll-like receptors (TLRs) play an important role in activating the immune response defense mechanisms to pathogens, including T. gondii. In mice, TLR9 appears to be an important defense against this parasite (Minns et al., 2006). T. gondii also appears to have evolved a counterattack mechanism, through which it blocks the effects of Toll receptor signaling (TLR2, TLR4 and TLR9) (Bennouna et al., 2006). Toll-like receptors activate a number of signaling pathways via the adaptor proteins MYD88 (myeloid differentiation primary response gene 88) and TIRAP (toll-interleukin 1 receptor [TIR] domain containing adaptor protein). These pathways include activation of the double-stranded DNA responsive eIF2-α kinase PKR (EIF2AK2) (Horng et al., 2001). This viral-activated kinase is one of a series of stress-responsive kinases that shut...  Read more


View all comments by Chris Carter

Comment by:  Fuller Torrey
Submitted 13 March 2007 Posted 13 March 2007

Chris Carter eloquently illustrates the many places where genes may interact with an infectious agent such as T. gondii. Regarding veterinary journals, we have in fact had interest in our work from this group but have elected to submit the majority of our papers to infectious disease journals.

View all comments by Fuller Torrey


Comment by:  John McGrath, SRF Advisor
Submitted 12 March 2007 Posted 14 March 2007

This paper is a good demonstration of the utility of systematic reviews and meta-analysis (Torrey et al., 2006). The review has identified several previously neglected studies. Furthermore, the synthesis of the data clearly shows that we have a good epidemiological signal here. Those with schizophrenia are significantly more likely to have serological markers of past T. gondii exposure.

As an aside, the data is also a testament to the tenacity and skills of the authors of this study—an initial hypothesis related to cat exposure has been buttressed by a convincing array of data (42 studies from 17 countries). This is an impressive collection of data for any field of risk factor epidemiology. While new hypotheses often strike ideological resistance, good data are harder to ignore.

Not only are individuals with schizophrenia more likely than controls to be seropositive for T. gondii, there is evidence that early life exposure is associated with an increased risk of later...  Read more


View all comments by John McGrath

Comment by:  Mary Reid
Submitted 27 March 2007 Posted 29 March 2007

A study by Tabbara and colleagues (Tabbara et al., 2001) reports an increased risk of Toxoplasma gondii infection in those with glucose-6-phosphate dehydrogenase deficiency. In view of the fact that glucose-6-phosphate dehydrogenase (G6PD) deficiency has been associated with acute psychosis, catatonic schizophrenia, and bipolar disorders (Bocchetta, 2003), I wonder whether it is actually the enzyme deficiency that causes these signs or the consequence of the infection. Chaudhary et al. comment (Chaudhary et al., 2005) on the fact that T.gondii cannot synthesize purines de novo and possesses two redundant purine salvage pathways involving the enzymes hypoxanthine-xanthine-guanine phosphoribosyltransferase (HXGPRT)1 and adenosine kinase. It's interesting that reduced adenosine A2A receptor expression with greatly increased...  Read more


View all comments by Mary Reid

Comment by:  Huan Ngo
Submitted 9 April 2007 Posted 9 April 2007

I am delighted to read this discussion, because as captivated as I have been by the proposed hypothesis of chronic Toxoplasma infection as a risk factor of schizophrenia, it brings to light some of the areas that need to be addressed, such as....

1. Prevalence of Toxoplasma seropositivity differs significantly across the globe, up to 75 percent in France, ~30 percent in the US, ~10 percent in Norway (Sukthana, 2006), depending on the cultural and hygienic practices. Why is the frequency of schizophrenia consistently ~1 percent across the board according to conventional dogma—but see current SRF Live Discussion. If an answer is genetic susceptibility, then how? If the next answer is epigenetic susceptibility, then which regions of which chromosomes are affected by Toxoplasma infection that contains the relevant clusters of risk alleles?

2. Since there is a complex array of susceptibility...  Read more


View all comments by Huan Ngo

Comment by:  Fuller Torrey
Submitted 11 April 2007 Posted 11 April 2007

Dr. Ngo raises many questions, for most of which there are currently no good answers. There are several possible reasons why the incidence of schizophrenia may not correlate well with the incidence of individuals who have antibodies to this organism. Genetic predisposition, as Dr. Ngo notes, is certainly one, and it is of interest that many of the genes that have been identified in relationship to schizophrenia are genes that concern immunological function. Another is strain differences in T. gondii, with some strains being more neurotropic than others. Another variable is mode of infection, as it is unclear if infection by tissue cyst (e.g., eating undercooked lamb) produces the same result as infection by oocyst (e.g., inhaling spores from dried cat feces).

A potentially important variable is the timing of the infection. Polio is a classic example of an infectious agent that causes no sequelae when infection takes place in early childhood but may cause severe problems when infection takes place in late childhood. Finally is possible co-infection, since there are...  Read more


View all comments by Fuller Torrey

Comment by:  Mary Reid
Submitted 12 April 2007 Posted 14 April 2007

Reply to Dr. Ngo:

You have asked why do most congenital toxoplasmosis cases not develop schizophrenia. Levy and colleagues (2006) report relatively high adenosine concentrations in neonatal blood plasma. If the auxotroph hypothesis is correct, then I wonder whether these high levels are protective?

It begs the question, does it require a double hit as suggested by Dr Torrey? Perhaps increased adenosine deaminase activity due to a further immune challenge depletes adenosine stores with an eventual immunodeficiency state.

View all comments by Mary Reid


Comment by:  Carla Gallo
Submitted 22 June 2007 Posted 22 June 2007

As stated in the previous commentaries, the article by Torrey and collaborators (Torrey et al., 2007) constitutes a step forward in the knowledge of the biological relationship between T. gondii and schizophrenia, for it brings solid evidence on the association of seropositivity to toxoplasma and the risk to develop schizophrenia. Nevertheless, it is a consensus that several important questions remain to be answered. These questions start with causality, and include timing of exposure, the underlying molecular mechanisms, and their modulating factors.

Important contributions to clarifying the timing issues are those of Brown et al. (2005) and Mortensen et al. (2007) on the role of in utero and early exposure to T. gondii for schizophrenia risk. Also, it should be very important to perform studies like those of Joram Feldon’s group that, simulating the immune challenge by certain viruses and bacteria through the activation...  Read more


View all comments by Carla Gallo
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