Antibodies to Infectious Agents in Individuals at Ultra-High Risk for Psychosis G. Paul Amminger, Patrick D. McGorry, Gregor E. Berger, Darryl Wade, Alison R. Yung, Lisa J. Phillips, Susy M. Harrigan, Shona M. Francey, and Robert H. Yolken Background: While there is evidence that some cases of schizophrenia may be associated with microbial infections, the role of microbial agents has not been investigated in people with emerging psychosis. Methods: Participants were 105 help seeking ultra-high risk individuals. Psychiatric measures included the Brief Psychiatric Rating Scale and the Scale for the Assessment of Negative Symptoms. Serum IgG antibodies against human herpesviruses and Toxoplasma gondii were determined using immunoassay methods. Multiple linear regression with adjustment for age and sex was applied to test associations between serum antibodies and psychiatric measures. Results: Higher levels of serum IgG antibodies against Toxoplasma gondii in Toxoplasma-positive individuals were significantly associated with more severe positive psychotic symptoms. No significant association was observed between antibody levels and psychiatric measures in individuals positive for human herpesviruses. Conclusions: In some individuals infection with Toxoplasma gondii may be an environmental factor contributing to the manifestation of positive psychotic symptoms. Key Words: Human herpes viruses, onset of psychosis, positive symptoms, schizophrenia, toxoplasma gondii, ultra-high risk A growing body of serological studies suggests that some cases of schizophrenia may be associated with exposure to microbial infections (Buka et al 2001; Brown et al 2001, 2004, 2005; Leweke et al 2004; Yolken et al 2001). Recent studies in people with schizophrenia have focused on members of the human herpesvirus family and the protozoan organism Toxo- plasma gondii because of their ability to establish persistent infection within the central nervous system as well as the occurrence of neurological and psychiatric symptoms in some individuals infected with these agents (Torrey and Yolken 2003; Yolken 2004). While microbial agents have been investigated in patients with established schizophrenia, the role of infectious agents for the onset of psychotic symptoms is unclear. We examined the relationship between serum antibodies against human herpesviruses and Toxoplasma gondii and measures of psychopathology in individuals at ultra-high risk for psychosis. Methods and Materials Participants All participants (n = 105; 39.0% male) (mean age = 19.1 years, SD = 3.2) were consecutively admitted to the Personal Assistance and Crises Evaluation (PACE) clinic in Melbourne, Australia, between April 2001 and December 2004. The criteria for identification of the ultra-high risk cohort and the rationale for these criteria have been previously described (McGorry et al 2002; Yung et al 1998). The participants met the criteria for at least one of three groups at intake, characterized by specific state and/or trait risk factors for psychosis. The three groups were: 1) trait plus state risk factors (i.e., genetic risk plus decrease in functioning), 2) attenuated symptoms, and 3) brief, limited intermittent psychotic symptoms. The criteria met by the subjects were as follows: trait plus state, 21.0%; attenuated symptoms, 85.7%; brief, limited intermittent psychotic symptoms, 9.5%. All participants were between the ages of 14 and 29 years, had not experienced a previous psychotic episode (treated or untreated), and reported English as the preferred language. The present study was approved by the North-Western Mental Health Pro- gram Research and Ethics Committee (Melbourne, Australia). All participants provided written informed consent, including paren- tal consent for those less than 18 years of age. Measures The Brief Psychiatric Rating Scale (BPRS) (Overall and Gorham 1962), the Scale for Assessment of Negative Symptoms (SANS) (Andreasen 1982) and the Global Assessment of Functioning (GAF) (DSM-IV) were used to assess psychopathology and functioning. Serum IgG class antibodies were measured to Herpes Simplex Virus Type 1 (HSV-1), Herpes Simplex Virus Type 2 (HSV-2), Cytomega- lovirus (CMV), Epstein Barr Virus (EBV), Varicella-Zoster Virus (VZV), and Toxoplasma gondii using previously described immu- noassay methods (Buka et al 2001; Yolken et al 2001). For each assay, a result was defined as positive or negative based on comparison with the reactivity of specific antibody standards as- sayed along with the blood samples. In the case of antibodies to the herpesviruses, these standards consisted of samples with defined levels of reactivity to the specific herpesvirus antigens (Sauerbrei and Wutzler 2004). In the case of antibodies to Toxoplasma gondii, this standard consisted of samples corresponding to 10 international units of antibody (Cubitt et al 1992; Rigsby et al 2004). Blood samples and psychopathology measures were obtained within 3 weeks after acceptance to the PACE clinic. All serological tests were carried out at the Stanley Laboratory of Developmental Neurovirol- ogy, Baltimore, Maryland. Statistical Analysis Multiple linear regression analyses with adjustment for age and sex were applied to investigate associations between IgG antibodies against infectious agents and psychiatric measures. First the predic- tive effects of seropositivity versus seronegativity were determined. If significant, subsequent analyses were carried out in seropositive individuals using continuous antibody concentrations as predictors From the ORYGEN Research Centre (incorporating the Personal Assistance and Crises Evaluation [PACE] Clinic) (GPA, PDM, GEB, DW, ARY, LJP, SMH, SMF), Department of Psychiatry, University of Melbourne, Australia; Department of Child and Adolescent Psychiatry (GPA), Medical University of Vienna, Austria; and the John Hopkins University School of Medicine (RHY), Stan- ley Division of Developmental Neurovirology, Baltimore, Maryland. Address reprint requests to Dr. G. Paul Amminger, Department of Child and Adoles- cent Psychiatry, Medical University of Vienna, Waehringer Guertel 18-20, A-1090 Vienna, Austria; E-mail: paul.amminger@meduniwien.ac.at. Received November 12, 2005; revised September 26, 2006; accepted Sep- tember 29, 2006. BIOL PSYCHIATRY 2007;xx:xxx 0006-3223/07/$32.00 doi:10.1016/j.biopsych.2006.09.034 © 2007 Society of Biological Psychiatry ARTICLE IN PRESS