V.     Studies of T. gondii Antibodies in Schizophrenia

     Studies of antibodies in individuals who have schizophrenia

The first 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.

Since Kozar’s 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 2011 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 2.73 (2.21–3.38) (Torrey EF, Bartko JJ, Yolken RH, Toxoplasma gondii: meta-analysis and assessment as a risk factor for schizophrenia, submitted for publication). 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).

    Studies 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). A large study of this military cohort failed to replicate the findings of this initial study (data not yet published).

In another 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).

Another study 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).

     Studies of antibodies in newborn children who later develop schizophrenia

In Denmark, 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 Psychiatry 2007;61:688–693).

    Studies 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 Psychiatry 2005;162:767–773).

    Are increased antibodies to T. gondii found in other psychiatric and/or neurological conditions?

It appears 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). Similarly, 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). 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). Finally, a 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, in press).

    Do 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).