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      Evidence of increased exposure to Toxoplasma gondii in individuals with recent onset psychosis but not with established schizophrenia

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          Abstract

          A possible role for Toxoplasma gondii in the etiopathogenesis of schizophrenia is supported by epidemiological studies and animal models of infection. However, recent studies attempting to link Toxoplasma to schizophrenia have yielded mixed results. We performed a nested case-control study measured serological evidence of exposure to Toxoplasma gondii in a cohort of 2052 individuals. Within this cohort, a total of 1481 individuals had a psychiatric disorder and 571 of were controls without a psychiatric disorder. We found an increased odds of Toxoplasma exposure in individuals with a recent onset of psychosis (OR 2.44, 95% Confidence Interval 1.4–4.4, p < .003). On the other hand, an increased odds of Toxoplasma exposure was not found in individuals with schizophrenia or other psychiatric disorder who did not have a recent onset of psychosis. By identifying the timing of evaluation as a variable, these findings resolve discrepancies in previous studies and suggest a temporal relationship between Toxoplasma exposure and disease onset.

          Author summary

          The protozoan parasite Toxoplasma gondii has been previously associated with an increased risk of serious psychiatric disorders such as schizophrenia. However, this association has been found in some studies and not others. We examined whether the differences among previous studies might be explained by the timing of patient evaluation and testing. We found that individuals who were evaluated soon after the onset of psychosis had increased odds of exposure to Toxoplasma gondii as evidenced by the measurement of antibodies in their blood. However. we did not find an increased rate of exposure to Toxoplasma gondii in individuals who had a diagnosis of schizophrenia or bipolar disorder but who did not have recent onset psychosis. Our findings are consistent with Toxoplasma exposure occurring around the time of onset of psychiatric symptoms in individuals with schizophrenia. Our findings might lead to the evaluation of new methods for the early treatment of schizophrenia in some individuals.

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          Most cited references24

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          Beyond the association. Toxoplasma gondii in schizophrenia, bipolar disorder, and addiction: systematic review and meta-analysis.

          To perform a meta-analysis on studies reporting prevalence of Toxoplasma gondii (T. gondii) infection in any psychiatric disorder compared with healthy controls. Our secondary objective was to analyze factors possibly moderating heterogeneity.
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            Endochin-like quinolones are highly efficacious against acute and latent experimental toxoplasmosis.

            Toxoplasma gondii is a widely distributed protozoan pathogen that causes devastating ocular and central nervous system disease. We show that the endochin-like quinolone (ELQ) class of compounds contains extremely potent inhibitors of T. gondii growth in vitro and is effective against acute and latent toxoplasmosis in mice. We screened 50 ELQs against T. gondii and selected two lead compounds, ELQ-271 and ELQ-316, for evaluation. ELQ-271 and ELQ-316, have in vitro IC(50) values of 0.1 nM and 0.007 nM, respectively. ELQ-271 and ELQ-316 have ED(50) values of 0.14 mg/kg and 0.08 mg/kg when administered orally to mice with acute toxoplasmosis. Moreover, ELQ-271 and ELQ-316 are highly active against the cyst form of T. gondii in mice at low doses, reducing cyst burden by 76-88% after 16 d of treatment. To investigate the ELQ mechanism of action against T. gondii, we demonstrate that endochin and ELQ-271 inhibit cytochrome c reduction by the T. gondii cytochrome bc(1) complex at 8 nM and 31 nM, respectively. We also show that ELQ-271 inhibits the Saccharomyces cerevisiae cytochrome bc(1) complex, and an M221Q amino acid substitution in the Q(i) site of the protein leads to >100-fold resistance. We conclude that ELQ-271 and ELQ-316 are orally bioavailable drugs that are effective against acute and latent toxoplasmosis, likely acting as inhibitors of the Q(i) site of the T. gondii cytochrome bc(1) complex.
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              Drugs used in the treatment of schizophrenia and bipolar disorder inhibit the replication of Toxoplasma gondii.

              The exact mechanisms of action of some antipsychotics and mood stabilizers have not been elucidated. Response to these medications can vary among individuals. Recent studies indicate that infection with the parasite Toxoplasma gondii may contribute to the symptoms of schizophrenia in some individuals. We investigated commonly used antipsychotic and mood stabilizing medications for their ability to inhibit the replication of this organism. We employed a system for testing compounds for in vitro activity against T. gondii. Human fibroblasts (HFF) were treated with test compounds and then exposed to Toxoplasma that has been genetically modified to express cytoplasmic beta-galactosidase. Inhibition by the drugs was determined by spectrophotometric analysis of colorimetric reactions. We tested 12 neuroleptic compounds and found that of these, the antipsychotic haloperidol and the mood stabilizer valproic acid most effectively inhibit Toxoplasma growth in vitro. Valproic acid inhibited the parasite at a concentration below that found in the cerebrospinal fluid and blood of individuals being treated with this medication and displayed synergistic activity with haloperidol and with trimethoprim, an antibiotic commonly used to treat Toxoplasma infections.Several medications used to treat schizophrenia and bipolar disorder have the ability to inhibit the in vitro replication of T. gondii.
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                Author and article information

                Contributors
                Role: ConceptualizationRole: InvestigationRole: Writing – review & editing
                Role: ConceptualizationRole: InvestigationRole: MethodologyRole: Writing – review & editing
                Role: ConceptualizationRole: Data curationRole: SupervisionRole: Writing – review & editing
                Role: Editor
                Journal
                PLoS Negl Trop Dis
                PLoS Negl Trop Dis
                plos
                plosntds
                PLoS Neglected Tropical Diseases
                Public Library of Science (San Francisco, CA USA )
                1935-2727
                1935-2735
                6 November 2017
                November 2017
                : 11
                : 11
                : e0006040
                Affiliations
                [1 ] Stanley Division of Developmental Neurovirology, Department of Pediatrics. Johns Hopkins School of Medicine, Baltimore Md, United States of America
                [2 ] Stanley Medical Research Institute, Chevy Chase, Md, United States of America
                [3 ] Department of Psychology, Sheppard Pratt Health System, Baltimore Md, United States of America
                Hitit University, Faculty of Medicine, TURKEY
                Author notes

                EFT is employed by the Stanley Medical Research Institute, which is a non-profit organization dedicated to research in the psychiatric disorders. RY is a member of the Stanley Medical Research Institute Board of Directors and Scientific Advisory Board. The terms of this arrangement are being managed by the Johns Hopkins University in accordance with its conflict of interest policies.

                Author information
                http://orcid.org/0000-0001-9902-1554
                Article
                PNTD-D-17-00992
                10.1371/journal.pntd.0006040
                5690692
                29108011
                a9d9ba76-bece-4fb9-9d9f-f08de886d6e9
                © 2017 Yolken et al

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 26 June 2017
                : 15 October 2017
                Page count
                Figures: 1, Tables: 2, Pages: 10
                Funding
                Funded by: funder-id http://dx.doi.org/10.13039/100007123, Stanley Medical Research Institute;
                Award Recipient :
                Funded by: funder-id http://dx.doi.org/10.13039/100007123, Stanley Medical Research Institute;
                Award Recipient :
                The work was supported by the Stanley Medical Research Institute. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Biology and Life Sciences
                Organisms
                Eukaryota
                Protozoans
                Parasitic Protozoans
                Toxoplasma
                Medicine and Health Sciences
                Mental Health and Psychiatry
                Psychoses
                Medicine and Health Sciences
                Mental Health and Psychiatry
                Schizophrenia
                Medicine and Health Sciences
                Mental Health and Psychiatry
                Mood Disorders
                Bipolar Disorder
                Biology and Life Sciences
                Organisms
                Eukaryota
                Protozoans
                Parasitic Protozoans
                Toxoplasma
                Toxoplasma Gondii
                Medicine and Health Sciences
                Mental Health and Psychiatry
                Mood Disorders
                Depression
                Medicine and Health Sciences
                Diagnostic Medicine
                Research and Analysis Methods
                Mathematical and Statistical Techniques
                Statistical Methods
                Meta-Analysis
                Physical Sciences
                Mathematics
                Statistics (Mathematics)
                Statistical Methods
                Meta-Analysis
                Custom metadata
                vor-update-to-uncorrected-proof
                2017-11-16
                Data will be available from Dr. Robert Yolken. Lorraine Brando, Johns Hopkins School of Medicine, ryolken1@ 123456jhmi.edu . Some restrictions apply based on regulations regarding patient confidentiality.

                Infectious disease & Microbiology
                Infectious disease & Microbiology

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