metaanalysis
The association between Toxoplasma and the psychosis continuum in a general population setting
Lindgren, M., Torniainen-Holm, M., Harkanen, T., Dickerson, F., Yolken, R. H., Suvisaari, J.
Schizophrenia Research 2018; 193: 329-335
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Toxoplasma gondii infection is associated with increased risk for psychosis. However, the possible association between T. gondii and psychotic-like symptoms in the general adult population is unknown.
We investigated whether T. gondii is associated with psychotic-like symptoms and psychosis diagnoses using data from Health 2000, a large cross-sectional health survey of the Finnish general population aged 30 and above. Seropositivity to toxoplasma was defined as a cutoff of 50 IU/ml of IgG antibodies. Lifetime psychotic-like symptoms were identified with section G of the Composite International Diagnostic Interview, Munich version (M-CIDI). Symptoms were considered clinically relevant if they caused distress or help-seeking or there were at least three of them. Lifetime psychotic disorders were screened from the sample and were diagnosed with DSM-IV using SCID-I interview and information from medical records. All data were available for 5906 participants. We adjusted for variables related to T. gondii seropositivity (age, gender, education, region of residence, cat ownership, and C-reactive protein measuring inflammation) in regression models.
We found that T. gondii seropositivity was significantly associated with clinically relevant psychotic-like symptoms (OR 1.77, p = 0.001) and with the number of psychotic-like symptoms (IRR = 1.55, p = 0.001). The association between toxoplasma and diagnosed psychotic disorders did not reach statistical significance (OR 1.45 for schizophrenia).
In a large sample representing the whole Finnish adult population, we found that serological evidence of toxoplasma infection predicted psychotic-like symptoms, independent of demographic factors and levels of C-reactive protein. Toxoplasma infection may be a risk factor for manifestation of psychotic-like symptoms.
Prevalence of Toxoplasma gondii infection in diabetic patients in Makkah AL Mukarramah, Saudi Arabia
Khalil, M., Baothman, M., Alserhan, F., Almunyif, A., Alsharbe, G., Samaren, H., Deqnah, N., Al Malki, A., Al Harbi, W.
Tropical Biomedicine 2018; 3: 464-471
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Toxoplasmosis is a parasitic and zoonotic disease caused by Toxoplasma gondii. The disease has worldwide distribution and all people maybe under the risk of getting infected by the parasite. The overall aim of this research was to detect the prevalence rate of anti-Toxoplasma gondii IgM and IgG among diabetic patients in Makkah, Saudi Arabia. Blood samples were collected from diabetic patients. Toxo IgM and IgG combo rapid test cassette were used to screen the samples, and the results were confirmed by using Enzyme-Linked Immunosorbent Assay (ELISA) to detect anti-IgM and anti-IgG antibodies on the plasma of 90 diabetic patients who attended the mobile clinic or AL Noor hospital in Makkah area. The subject was asked to complete a structured questionnaire. The questionnaire data and serological results were analyzed by using SPSS 20. Chi-square was used to compare different variables. Out of 90 samples, 39 (43.3%) were positive to anti-Toxoplasma gondii IgG wherein 33 (36.6%) of them were male and 6 (6.7%) were female. The age ranged between 13-85 years with the mean of 49.9 years. The study found that there were statistical differences between the age groups with higher prevalence in the 50-65 years age group. Detection of IgM against T. gondii gave negative results. The results of the study indicate that latent T. gondii in diabetic patient are relatively high especially among the 50-65 age group. There were significant associated between direct contact with a cat and infection by T. gondii (p<0.05).
Immunoglobulin sub-class distribution in bipolar disorder and schizophrenia: potential relationship with latent Toxoplasma Gondii infection
Bengoufa, H. D., Godin, O., Doukhan, R., Guen, E. L.,Daban-Huard, C. , Bennabi, M., Delavest, M., Lepine, J. P., Boukouaci, W., Laouamri,H., Houenou, J., Jamain, S., Richard, J. R. , Lecorvosier, P. , Yolken, R., Rajagopal, K., Leboyer, M., Tamouza, R.
Bmc Psychiatry 2018; 18
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Background: Immune dysfunction could play a significant role in the pathogenesis of bipolar disorder (BD) and schizophrenia (SZ), conditions with an underlying pro-inflammatory state. Studies on humoral immune responses (which reflects antibody mediated fight against pathogens) in schizophrenia and bipolar disorder are sparse and often providing contradictory results. The aim of this study was to assess humoral immunity in a group of stable bipolar disorder and schizophrenia patients compared to controls by determining total Immunoglobulins and IgG subclasses and to assess their association with latent Toxoplasma gondii and/or CMV infection. Methods: 334 subjects (124 BD, 75 SZ and 135 Healthy Controls [HC]) were included and tested for humoral immunity by determining the total immunoglobulins (IgG,A and M) and IgG subclasses (IgG1, IgG2, IgG3, IgG4) and their relationship with latent Toxoplasma gondii infection, an established risk factor for BD and SZ. Results: Although lower levels of IgG, IgG1, IgG2, IgG4 and IgA were found among BD as compared to HC and/or SZ, after adjustment for confounding variables, only low levels of IgG and IgG1 in BD remai- ned significant. Strikingly highest levels of antibodies to T. gondii (but not CMV) infection in BD and SZ were associated with lowest levels of IgG3 and IgG4 levels as compared to controls. Conclusions: Schizophrenia and bipolar disorder patients with latent T. gondii specific infection may be more vulnerable to changes in immuno-inflammatory processes than controls with similar latent infectious state. Simultaneous sequential immunological monitoring both in steady state and active disease phases in the same BD and SZ patients are warranted to understand the role of Toxoplasma gondii latency in these disorders.
Toxoplasma gondii infection and behavioral outcomes in humans: a systematic review
Martinez, V. O. , Lima, F. W. D., . de Carvalho, C. F, Menezes, J. A.
Parasitology Research 2018; 117: 3059-3065
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Studies suggest that the protozoan Toxoplasma gondii can disturb human behavior. This study aimed to systematically review the scientific literature on the possible associations between Toxoplasma gondii infection and neurobehavioral abnormalities in humans. We reviewed and summarized the studies published since 1990. The descriptors used were related to T. gondii infection and behavioral outcomes in humans; the main databases of the medical literature were accessed. The results of eight original articles published between 1994 and 2016 were evaluated and described. The most common serological method was the enzyme immunoassay. Most of the researchers used validated instruments for behavioral evaluation. Seven studies reported some association between the prevalence of anti-T. gondii antibodies and some altered behavioral aspects in adult humans; these studies focused on adult population in Europe and the USA. The most reported behavioral deviations are related to greater impulsivity and aggressiveness. There are very few studies on this subject, which present some limitations for inference and conclusions: most were cross-sectional studies, with a small sample size and in similar populations. Investigations with a larger sample size of different population groups should be performed to evaluate multiple factors.
Immunoglobulin sub-class distribution in bipolar disorder and schizophrenia: potential relationship with latent Toxoplasma Gondii infection
Hamdani,N. ,Bengoufa, D. , Godin, O., Doukhan, R.., Le Guen,E., Daban-Huard, C. , Bennabi, M. ,Delavest, M., Lepine, J. P., Boukouaci, W. , Laouamri, H. , Houenou,J., Jamain, S., Richard,J. R. , Lecorvosier, P. , Yolken,R. , Rajagopal, K. , Leboyer, M. , Tamouza, R.
BMC Psychiatry,10.1186/s12888-018-1821-9, Article Number 239
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Background: Immune dysfunction could play a significant role in the pathogenesis of bipolar disorder (BD) and schizophrenia (SZ), conditions with an underlying pro-inflammatory state. Studies on humoral immune responses (which reflects antibody mediated fight against pathogens) in schizophrenia and bipolar disorder are sparse and often providing contradictory results. The aim of this study was to assess humoral immunity in a group of stable bipolar disorder and schizophrenia patients compared to controls by determining total Immunoglobulins and IgG subclasses and to assess their association with latent Toxoplasma gondii and/or CMV infection. Methods: 334 subjects (124 BD, 75 SZ and 135 Healthy Controls [HC]) were included and tested for humoral immunity by determining the total immunoglobulins (IgG,A and M) and IgG subclasses (IgG1, IgG2, IgG3, IgG4) and their relationship with latent Toxoplasma gondii infection, an established risk factor for BD and SZ. Results: Although lower levels of IgG, IgG1, IgG2, IgG4 and IgA were found among BD as compared to HC and/or SZ, after adjustment for confounding variables, only low levels of IgG and IgG1 in BD remai- ned significant. Strikingly highest levels of antibodies to T. gondii (but not CMV) infection in BD and SZ were associated with lowest levels of IgG3 and IgG4 levels as compared to controls. Conclusions: Schizophrenia and bipolar disorder patients with latent T. gondii specific infection may be more vulnerable to changes in immuno-inflammatory processes than controls with similar latent infectious state. Simultaneous sequential immunological monitoring both in steady state and active disease phases in the same BD and SZ patients are warranted to understand the role of Toxoplasma gondii latency in these disorders.
Association of Toxoplasma gondii infection with schizophrenia and its relationship with suicide attempts in these patients
Ansari-Lari, M., Farashbandi, H., Mohammadi, F.
Tropical Medicine and International Health 2017; 22: 1322-1327
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OBJECTIVES To investigate the association between schizophrenia and Toxoplasma gondii, and to assess the association of infection with suicide attempts and age of onset of schizophrenia in these patients. METHODS Case-control study Fars Province, southern Iran. Cases were individuals with psychiatric diagnosis of schizophrenia as per Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) criteria. Controls were healthy blood donors, frequency-matched with patients according to age and sex. For the detection of IgG antibodies, enzyme-linked immunosorbent assay (ELISA) was used. Data about demographic information in all subjects and duration of illness and history of suicide attempts in patients with schizophrenia were collected using a brief questionnaire and hospital records. Chi-square test and multivariable logistic regression were used for statistical analyses. RESULTS Among 99 cases, 42 individuals (42%) were positive for T. gondii antibody, vs. 41 (27%) among 152 controls (OR = 2, 95% CI: 1.2-3.4, P = 0.012). We compared the suicide attempts in patients with schizophrenia based on their T. gondii serologic status. There was a lower rate of suicide attempts in seropositive male patients than seronegative ones (OR = 0.3, 95% CI: 0.1-0.97, P = 0.04). Age of onset of schizophrenia did not differ between T. gondii-infected and non-infected patients. CONCLUSIONS These findings may have implications for schizophrenia and suicide prevention programmes. However, clearly further studies are required to confirm them.
Toxoplasma gondii moderates the association between multiple folate-cycle factors and cognitive function in US adults
Berrett, A. N., Gale, S. D., Erickson, L. D., Brown, B. L., Hedges, D. W.
Nutrients 2017; 9
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Toxoplasma gondii (T. gondii) is a microscopic, apicomplexan parasite that can infect muscle or neural tissue, including the brain, in humans. While T. gondii infection has been associated with changes in mood, behavior, and cognition, the mechanism remains unclear. Recent evidence suggests that T. gondii may harvest folate from host neural cells. Reduced folate availability is associated with an increased risk of neurodevelopmental disorders, neurodegenerative diseases, and cognitive decline. We hypothesized that impairment in cognitive functioning in subjects seropositive for T. gondii might be associated with a reduction of folate availability in neural cells. We analyzed data from the third National Health and Nutrition Examination Survey to determine the associations between T. gondii infection, multiple folate-cycle factors, and three tests of cognitive functioning in U.S. adults aged 20 to 59 years. In these analyses, T. gondii moderated the associations of folate, vitamin B-12, and homocysteine with performance on the Serial Digit Learning task, a measure of learning and memory, as well as the association of folate with reaction time. The results of this study suggest that T. gondii might affect brain levels of folate and/or vitamin B-12 enough to affect cognitive functioning.
Parkinson’s disease and Toxoplasma gondii infection: Sero-molecular assess the possible link among patients
Fallahi, S., Rostami, A., Birjandi, M., Zebardast, N., Kheirandish, F., Spotin, A.
Acta Tropica 2017; 173: 97-101
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We investigated the possible association between Parkinson's disease (PD), the second most common neurode-generative disorder and Toxoplasma gondii infection, the most common neurotropic protozoan parasitic infection, using serological and molecular techniques. One hundred and fifteen patients with confirmed PD and 115 healthy subjects in the same age and sex distribution were enrolled in this study. Blood samples were taken from each participant and the sera was screened for anti-Toxoplasma antibodies (IgG and IgM). PCR assay was performed in duplicate using the primer pair targeting the B1 gene of Toxoplasma. Amplicons were directly sequenced to conduct the phylogenetic analysis. The prevalence of Toxoplasma infection based on IgG titer was 53% in case and 55.6% in the control groups, revealing no statistically significant association between Toxoplasma seropositivity and PD (OR = 0.90; 95% CI = 0.54-1.51; P = 0.691). According to PCR assay, the prevalence of Toxoplasma infections was 19.3% in the case and 10.4% in control groups which the difference was statistically significant (OR = 3.02; 95% CI = 1.46-6.27; P = 0.002). Multiple sequence alignment of Toxoplasma gondii isolates manifested a common haplotype by the identity: 93.6-100% and divergence: 0-6.7%. We concluded that T. gondii infection not only could not be a risk factor to PD, but even it could be concluded that patients with PD are in more risk to acquisition of infection. These results provide fresh insights into the ambiguous association between T. gondii infection and PD.
Toxoplasma gondii and schizophrenia: a review of published RCTs
Chorlton, S.D.
Parasitology Research 2017; 116: 1793-1799
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Over the last 60 years, accumulating evidence has suggested that acute, chronic, and maternal Toxoplasma gondii infections predispose to schizophrenia. More recent evidence suggests that chronically infected patients with schizophrenia present with more severe disease. After acute infection, parasites form walled cysts in the brain, leading to lifelong chronic infection and drug resistance to commonly used antiparasitics. Chronic infection is the most studied and closely linked with development and severity of schizophrenia. There are currently four published randomized controlled trials evaluating antiparasitic drugs, specifically azithromycin, trimethoprim, artemisinin, and artemether, in patients with schizophrenia. No trials have demonstrated a change in psychopathology with adjunctive treatment. Published trials have either selected drugs without evidence against chronic infection or used them at doses too low to reduce brain cyst burden. Furthermore, trials have failed to achieve sufficient power or account for confounders such as previous antipsychotic treatment, sex, age, or rhesus status on antiparasitic effect. There are currently no ongoing trials of anti-Toxoplasma therapy in schizophrenia despite ample evidence to justify further testing.
Toxoplasma gondii seroprevalence in a cohort of Italian psychiatric inpatients with mood or psychotic disorders: a preliminary communication
Del Grande, C., Schiavi, E., Masci, I., Barbuti, M., Maccariello, G., Pinto, B., Massimetti, G., Bruschi, F. , Dell’Osso, L.
European Neuropsychopharmacology 2017; 27: 881-882
Evidence of increased exposure to Toxoplasma gondii in individuals with recent onset psychosis but not with established schizophrenia
Yolken, R., Torrey, E.F., Dickerson, F.
PLOS Neglected Tropical Diseases 2017; 10.1371/journal.pntd.0006040
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AB 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.
The association between immune markers and recent suicide attempts in patients with serious mental illness: A pilot study
Dickerson, F., Adamos, M., Katsafanas, E., Khushalani, S., Origoni, A., Savage, C., Schweinfurth, L., Stallings, C., Sweeney, K., Alaedini, A., Uhde, M., Severance, E., Wilcox, H. C., Yolken, R.
Psychiatry Research 2017;255:8-12
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Previous studies have identified elevations in markers of gastrointestinal inflammation in schizophrenia and mood disorders but studies have not measured the association between these markers and recent suicide attempts. We assessed 210 patients receiving treatment for schizophrenia, bipolar disorder, or major depression. We employed the Columbia Suicide Severity Rating Scale to identify recent and lifetime suicide attempts (actual, aborted, and interrupted). Psychiatric participants and a control group of 72 individuals without a psychiatric disorder had a blood sample drawn from which were measured specific markers of gastrointestinal inflammation and also C-Reactive protein (CRP). A total of 20 (10%) of psychiatric participants had a suicide attempt in the previous one month and 95 (45%) an attempt during their lifetime but not in the previous one month. The recent attempters had significantly elevated levels of antibodies to yeast mannan from Saccharomyces cerevisiae (ASCA), the food antigen gliadin, and bacterial lipopolysaccharide (LPS) compared with the non-psychiatric group when adjusting for demographic and clinical variables. These markers were not elevated in individuals with a past, but not recent, suicide attempt history. Our study indicates that there is evidence of gastrointestinal inflammation in some individuals who have had a recent suicide attempt.
Infection and inflammation in schizophrenia and bipolar disorder
Tanaka, T., Matsuda, T., Hayes, L. N., Yang, S. J., Rodriguez, K., Severance, E. G., Yolken, R. H., Sawa, A., Eaton, W. W.
Neuroscience Research 2017; 115: 59-63
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The present study investigated the relationship between exposure to infectious agents and inflammation markers in individuals with schizophrenia (SZ), bipolar disorder (BP), and controls without a psychiatric disorder. We measured plasma levels of antibodies and innate immune markers and correlated them with clinical symptoms and cognitive function. In both SZ and BP, we found an increase in soluble CD14, and in BP an increase in C-reactive protein, IgM class antibodies against cytomegalovirus (CMV), and IgG class antibodies against herpes simplex virus 2. Furthermore in BP, we observed a negative relationship between IgG antibodies against CMV and scores for cognitive function. (C) 2016 Elsevier Ireland Ltd and Japan Neuroscience Society. All rights reserved.
Bipolar disorder with psychotic features and ocular toxoplasmosis
Del Grande, C., Contini, C., Schiavi, E., Rutigliano, G., Maritati, M., Seraceni, S., Pinto, B., Dell'Osso, L., Bruschi, F.
Journal of Nervous and Mental Disease 2017; 205: 192-195
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Recent evidence suggests the involvement of Toxoplasma gondii infection in the emergence of psychotic and affective disorders. In this report, we describe the case of a young Brazilian woman affected by recurrent ocular toxoplasmosis and presenting with a manic episode with psychotic features in the context of a diagnosis of Bipolar Disorder (BD), type I. We observed a relationship between ocular manifestations and the clinical course of bipolar illness, confirmed by molecular analyses (nested-PCR), as well as by the high level of T. gondii specific IgG. This case report is the first showing the presence of circulating parasite DNA at the time of occurrence of psychiatric symptoms, thus providing further support for a possible role of the parasite in the pathogenesis of some cases of BD.
Toxoplasma gondii infection and common mental disorders in the Finnish general population
Suvisaari, J., Torniainen-Holm, M., Lindgren, M., Harkanen, T., Yolken, R. H.
Journal of Affective Disorders 2017; 223: 20-25
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Objective: We investigated whether T. gondii seropositivity is associated with 12-month depressive, anxiety and alcohol use disorders and current depressive symptoms and whether inflammation, measured by C-reactive protein (CRP) level, explains these associations.
Method: Health 2000 study (BRIF8901), conducted in years 2000-2001, is based on a nationally representative sample of Finns aged 30 and above, with 7112 participants and 88.6% response rate. DSM-IV depressive, anxiety and alcohol use disorders were assessed with the Composite International Diagnostic Interview and depressive symptoms with the Beck Depressive Inventory (BDI-21). We used logistic regression to investigate the association of T. gondii seropositivity with mental disorders and linear regression with BDI-21 scores.
Results: T. gondii seroprevalence was significantly associated with 12-month generalized anxiety disorder but not with other anxiety, depressive or alcohol use disorders. T. gondii seropositivity was associated with higher BDI-21 scores (beta 0.56, 95% CI 0.12-1.00, P = 0.013) and with having a comorbid depressive and anxiety disorder (OR 1.86, 95% CI 1.16-2.97, P = 0.010). Higher CRP levels were associated with these outcomes and with T. gondii seropositivity, but adjusting for CRP did not change the effect of T. gondii seropositivity.
Limitations: Cross-sectional study design with no information on the timing of T. gondii infection.
Conclusion: T. gondii seropositivity is associated with generalized anxiety disorder, depressive symptoms and comorbid depressive and anxiety disorders, which is not mediated by inflammation.
Toxoplasma gondii infection in schizophrenia and associated clinical features
Esshili, A., Thabet, S., Jemli, A., Trifa, F., Mechri, A., Zaafrane, F., Gaha, L., Juckel, G., Babba, H., Jrad, B. B. H.
Psychiatry Research 2016; 245: 327-332
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The belief that latent toxoplasmosis is asymptomatic has been questioned, in particular due to the repeated highlighted link between the Toxoplasma gondii infection and an increased incidence of schizophrenia. However, to understand this relationship, the effect of infection with Toxoplasma gondii on the severity of schizophrenia has been poorly studied. Our work focused on comparing the prevalence of Toxoplasma infection between schizophrenic patients and healthy controls, as well as comparing the clinical features and the demographic characteristics between Toxoplasma-seronegative and Toxoplasma-seropositive patients with schizophrenia. The rate of IgG antibody in the schizophrenia patients was 74.8% compared 53.8% in controls. Patients with schizophrenia had a significantly higher mean of serum IgG antibodies to T. gondii compared to controls. The seropositive male patients had a higher age of disease onset, a higher BPRS score, a greater negative PANSS score and a lower GAF score than the seronegative male patients. These results suggest a higher severity of clinical symptoms in the male patients with schizophrenia. This study provides further evidence to the hypothesis that exposure to Toxoplasma may be a risk factor for schizophrenia. Moreover, toxoplasmosis in men with schizophrenia may lead to more severe negative and cognitive symptoms and a less favorable course of schizophrenia.
No association between current depression and latent toxoplasmosis in adults
Gale, S. D., Berrett, A. N., Brown, B., Erickson, L. D., Hedges, D. W.
Folia Parasitologica 2016; 63: DOI 10.14411/fp.2016.032
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Changes in behaviour and cognition have been associated with latent infection from the apicomplexan protozoan Toxoplasma gondii (Nicolle et Manceaux, 1908) in both animal and human studies. Further, neuropsychiatric disorders such as schizophrenia have also been associated with latent toxoplasmosis. Previously, we found no association between T. gondii immunoglobulin G antibody (IgG) seropositivity and depression in human adults between the ages of 20 and 39 years (n = 1 846) in a sample representative of the United States collected by the Centers for Disease Control as part of a National Health and Nutrition Examination Survey (NHANES) from three datasets collected between 1999-2004. In the present study, we used NHANES data collected between 2009 and 2012 that included subjects aged 20 to 80 years (n = 5 487) and used the Patient Health Questionnaire 9 (PHQ-9) to assess depression with the overall aim of testing the stability of the results of the prior study. In the current study, the seroprevalence of T. gondii was 13%. The percentage of subjects reporting clinical levels of depression assessed with the PHQ-9 was 8%. As before, we found no association between T. gondii IgG seroprevalence and depression (OR = 1.01, 95% CI = 0.81-1.25; p = 0.944) while controlling for sex, educational attainment, race-ethnicity, age, poverty-to-income ratio and cigarette smoking. We also found no positive associations between anti-T. gondii antibody titre and depression (OR = 1.00, 95% CI = 0.96-1.06; p = 0.868). Moreover, we found no association between T. gondii seroprevalence or antibody titre and suicidal ideation (seroprevalence: OR = 1.22, 95% CI =.85-1.75; p = 0.277, titre: OR = 1.05, 95% CI = 0.98-1.14; p = 0.177). Defining depression to also include subjects currently taking antidepressant medication even with non-elevated questionnaires did not find evidence of a positive association between latent toxoplasmosis and depression. In the present study, neither T. gondii seroprevalence nor anti-T. gondii antibody titre was positively associated with depression or suicidal ideation among subjects aged 20 to 80 years.
Exposure to perinatal infections and bipolar disorder: A systematic review
Barichello, T., Badawy, M., Pitcher, M. R., Saigal, P., Generoso, J. S., Goularte, J. A., Simoes, L. R., Quevedo, J., Carvalho, A. F.
Curr Mol Med 2016; 16: 106-118
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Bipolar disorder (BD) is a debilitating psychiatric disorder and a growing global public health issue. Notwithstanding BD has been conceptualized as a neuroprogressive illness, there are some evidences to suggest a role for neurodevelopmental pathways in the patho-etiology of this disorder. Evidences on the associations between perinatal infections and risk for bipolar disorder have been inconsistent across studies. Here, we performed a systematic review of observational studies on the relationship between exposure to perinatal pathogens and bipolar disorder. A computerized literature search of the PubMed, Embase, and PsyINFO databases till January 31st, 2015 was performed. Twenty-three studies ultimately met inclusion criteria. Studies investigated exposure to several pathogens namely Cytomegalovirus (CMV), Epstein-Barr Virus (EBV), Herpes simplex virus-1 (HSV-1), Herpes simplex virus-2 (HSV-2), Human herpesvirus 6 (HHV-6), Toxoplasma gondii, Influenza, and Varicella zoster virus (VZV). Overall, studies provided mixed evidences. Thus, contrary to schizophrenia, the role of perinatal infections as risk factors for BD remain inconclusive. Larger studies with a prospective design would be necessary to elucidate the role of previous exposure to infectious agents as a potential risk factor for BD.
Relationship of Toxoplasma Gondii Exposure with Multiple Sclerosis
Oruc, S.
European Journal of General Medicine, 2016, 13: 58-63
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Objective: Toxoplasma gondii infection is a very common parasitic disease in human. In Turkey, the rate of seropositivity was reported as 23.1% to 36%. Because of the high affinity of parasite into Central Nervous System (CNS), chronic toxoplasma infection has been found correlated with many neuropsychiatric disorders, including altered mental status, obsessive-compulsive disorder, cognitive impairment, epilepsy, headache and schizophrenia. In this study, we aimed to investigate whether T. gondii has any role in Multiple Sclerosis (MS) by measuring anti-T. gondii IgG antibodies. Methods: Fifty-two MS patients followed up and 45 controls with similar age and socioeconomic status were included in the study. Anti-T. gondii IgL antibodies of the patients and controls were studied in blood with micro-enzyme-linked immunosorbent assay (ELISA) technique. Results: Of 52 MS patients included in the study, 37 had RRMS, 10 PPMS and 5 SPMS. Mean age of onset of the disease was 31.7 +/- 10.4 (min; 14 and max; 53). Twenty three of 52 (44.2%) cases with MS and 11 of 45 (24.4%) healthy controls were positive for anti-T. gondii IgG antibodies. There was a statistically significant difference between the rates of positivity between the MS patient group and control group (p=0.042). Conclusion: This study shows a relation of chronic T. Gondii infection with MS. According to this study, experienced T. gondii infection may be one of the several environmental risk factors for MS.
The correlation between Toxoplasma gondii infection and prenatal depression in pregnant women
Shiadeh, M. N., Rostami, A., Pearce, B. D., Gholipourmalekabadi, M., Newport, D. J., Danesh, M., Mehravar, S., Seyyedtabaei, S. J.
European Journal of Clinical Microbiology & Infectious Diseases 2016; 35: 1829-1835
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Previous studies have demonstrated that latent toxoplasmosis is associated with neuropsychiatric disorders. We evaluated the correlation between Toxoplasma gondii infection and prenatal depression. In this case-control study, we enrolled 116 depressed pregnant women and 244 healthy controls. The Edinburgh Postpartum Depression Scale (EPDS) was used to evaluate the depression symptom severity in study participants. All participants were screened for the anti-Toxoplasma IgG by enzyme-linked immunosorbent assay. Seroprevalence of T. gondii did not significantly differ between the depressed pregnant women and healthy controls (OR = 1.4; 95 % CI = 0.9-2.19; P = 0.142). T. gondii IgG titer was significantly higher in depressed women (18.6 +/- 10.9 IUs) than those in the control group (13.6 +/- 8.1 IUs) (z = -5.36, P < 0.001). The T. gondii-positive depressed women showed a positive correlation of T. gondii IgG titer with the EPDS scores (r = 0.52; P < 0.01). The mean EPDS score was also significantly higher in the T. gondii-positive depressed women (20.7 +/- 2.7) compared with the controls (18.36 +/- 2.7) (P < 0.001). The results obtained from the current study revealed that T. gondii infection might affect susceptibility to depression and severity of depressive symptoms in pregnant women, particularly in those patients who have high antibody titers. Further study is required to fully elucidate the characteristics and mechanisms of this association.
Assessment of Toxoplasma sweropositivity in children suffering from attention deficit hyperactivity disorder
Afsharpaiman, S., Khosravi, M. H., Faridchehr, M., Komijani, M., Radfar, S., Amirsalari, S., Torkaman, M., Shirbazoo, S.
Galen Medical Journal 2016; 5: 188-193
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Background: Toxoplasmosis, a protozoan infection caused by Toxoplasma gondii, is suggested to be a risk factor for many psychological disorders such as schizophrenia and depression. Attention deficit hyperactivity disorder (ADHD) is one of the most common psychiatric disorders among children. Previous studies have assessed the correlation between ADHD and infectious diseases like toxoplasmosis. So we aimed to investigate the possible correlation between Toxoplasma seropositivity and ADHD in children. Materials and Methods: In this cross-sectional study children with signs of ADHD were regarded as patients and underwent clinical assessments. Diagnosis of these patients was based on DSM-IV-TR system which was performed by a pediatric psychiatrist. Forty-eight Children without signs of ADHD or other psychic disorders were considered as control, and 48 patients were considered as case group. Parents were asked to answer a questionnaire including demographic, pregnancy and habitual questions. Blood samples were taken from all individuals and assessed for anti-Toxoplasma IgM and IgG antibodies. Results: Ninety-six male and female patients with a mean age of 8.12 years underwent analysis. Seropositivity rate for anti-T.gondii IgG antibody was 4.2% in the case and 2.1% in control individuals (P=0.92). Anti-T.gondii IgM antibodies were not found in control individuals while it was found in 2.1% of case individuals (P=0.74). There was no statistically significant association between seroprevalence of IgM (P=0.74) and IgG (P=0.92) antibodies and ADHD in study individuals. Conclusion: Our findings showed that the toxoplasmosis seropositivity has no significant difference between children with and without ADHD. Further studies are needed with a larger amount of individuals.
Treatment with anti-toxoplasmic activity (TATA) for Toxoplasma positive patients with bipolar disorders or schizophrenia: A cross-sectional study
Fond, G., Boyer, L., Gaman, A., Laouamri, H., Attiba, D., Richard, J. R., Delavest, M., Houenou, J., Le Corvoisier, P., Charron, D., Krishnamoorthy, R., Oliveira, J., Tamouza, R., Yolken, R., Dickerson, F., Leboyer, M., Hamdani, N.
Journal of Psychiatric Research 2015; 63: 58-64.
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Objective: The association between Toxoplasma gondii seropositivity and respectively Bipolar Disorder (BD) and Schizophrenia/Schizoaffective disorder (SZ) is one of the most studied link between one pathogen and psychiatric disorders. The aim of the present study was thus to retrospectively determine if the administration of an antipsychotic and/or a mood stabilizer having known in vitro Anti-Toxoplasmic Activity (TATA+) was associated with a better clinical outcome in a population of 152 BD or 114 SZ patients and seropositive for T gondii infection compared to patients receiving a treatment without anti-toxoplasmic activity (TATA-).
Methods: This multicenter study was conducted in an academic public hospital during a 3-years period between 2009 and 2011. All consecutive inpatients and outpatients with SZ or BD diagnosis with a stable treatment for more than 4 weeks were recruited. socio-demographic and clinical characteristics measured with validated scales as well as a serological status for toxoplasmic infection were included. Treatments were classified according to their in vitro antitoxoplasmic activity. A multivariate model was used to determine the clinical characteristics that were significantly different between patients receiving a treatment with no antitoxoplasmic activity compared to others.
Results: BD patients with positive serum antibodies against T gondii presented more lifetime depressive episodes (p = 0.048) after adjustment forage, sex and sociodemographic characteristics when treated by drug having no anti-toxo activity, compared to patients having received drugs with anti-toxo activity. A significant difference was not found in BD toxonegative patients and in SZ toxopositive or toxonegative patients.
Conclusions: It seems to be of importance to consider prescribing a drug with a clear anti-toxoplasmic activity (TATA+) for BD patients seropositive to T. gondii, in particular valproate that was found as the mood stabilizer with the highest antitoxoplasmic activity. Prospective randomized controlled trials are warranted to confirm this preliminary data.
Toxoplasma gondii and anxiety disorders in a community-based sample
Markovitz, A. A., Simanek, A. M., Yolken, R. H., Galea, S., Koenen, K. C., Chen, S., Aiello, A. E.
Brain Behavior and Immunity 2015; 43: 192-197
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A growing body of literature suggests that exposure to the neurotropic parasite Toxoplasma gondii (T. gondii) is associated with increased risk of mental disorders, particularly schizophrenia. However, a potential association between T. gondii exposure and anxiety disorders has not been rigorously explored. Here, we examine the association of T. gondii infection with both anxiety and mood disorders. Participants (n = 484) were drawn from the Detroit Neighborhood Health Study, a population-representative sample of Detroit residents. Logistic regression was used to examine the associations between T. gondii exposure (defined by seropositivity and IgG antibody levels) and three mental disorders: generalized anxiety disorder (GAD), posttraumatic stress disorder (PTSD) and depression. We found that T. gondii seropositivity was associated with a 2 times greater odds of GAD (odds ratio (OR). 2.25: 95% confidence interval (CI), 1.11-4.53) after adjusting for age, gender, race, income, marital status, and medication. Individuals in the highest antibody level category had more than 3 times higher odds of GAD (OR, 3.35: 95% Cl, 1.41-7.97). Neither T. gondii seropositivity nor IgG antibody levels was significantly associated with PTSD or depression. Our findings indicate that T. gondii infection is strongly and significantly associated with GAD. While prospective confirmation is needed, T. gondii infection may play a role in the development of GAD.
Seropositivity and serointensity of Toxoplasma gondii antibodies and DNA among patients with schizophrenia
Omar, A., Bakar, O. C., Adam, N. F., Osman, H., Osman, A., Suleiman, A. H., Manaf, M. R. A., Selamat, M. I.
Korean Journal of Parasitology 2015; 53: 29-34.
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The aim of this cross sectional case control study was to examine the serofrequency and serointensity of Toxoplasma gondii (Tg) IgG, IgM, and DNA among patients with schizophrenia. A total of 101 patients with schizophrenia and 55 healthy controls from Sungai Buloh Hospital, Selangor, Malaysia and University Malaya Medical Center (UMMC) were included in this study. The diagnosis of schizophrenia was made based on the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV). The presence of Tg infection was examined using both indirect (ELISA) and direct (quantitative real-time PCR) detection methods by measuring Tg IgG and IgM and DNA, respectively. The serofrequency of Tg IgG antibodies (51.5%, 52/101) and DNA (32.67%, 33/101) among patients with schizophrenia was significantly higher than IgG (18.2%, 10/55) and DNA (3.64%, 2/55) of the controls (IgG, P=0.000, OD=4.8, CI=2.2-10.5; DNA, P=0.000, OD=12.9, CI=2.17-10.51). However, the Tg IgM antibody between patients with schizophrenia and controls was not significant (P>0.005). There was no significant difference (P>0.005) in both serointensity of Tg IgG and DNA between patients with schizophrenia and controls. These findings have further demonstrated the strong association between the active Tg infection and schizophrenia.
Immune alterations in acute bipolar depression
Dickerson, F., Katsafanas, E., Schweinfurth, L. A. B., Savage, C. L. G., Stallings, C., Origoni, A., Khushalani, S., Lillehoj, E., Yolken, R.
Acta Psychiatrica Scandinavica 2015; 132: 204-210
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Objective immunologic abnormalities have been found in bipolar disorder and acute mania. However, there have been fewer studies of patients with acute bipolar depression.
MethodBlood samples were obtained from individuals with acute bipolar depression, acute mania, and controls. These samples were evaluated for antibodies to human herpesviruses, gliadin, Toxoplasma gondii, and endogenous retroviruses as well as for C-reactive protein (CRP) and pentraxin-3 using immunoassay methods. Linear regression models were used to compare the levels of the markers controlling for demographic and clinical variables. A subset of the bipolar depressed group was evaluated at a 6-month follow-up.
ResultsThe sample consisted of 82 individuals with acute bipolar depression, 147 with acute mania, and 280 controls. The levels of CRP and IgG antibodies to an endogenous retrovirus, Mason-Pfizer monkey virus (MPMV), were significantly elevated in the bipolar depressed group. Levels of pentraxin-3 were reduced in both psychiatric groups. An evaluation of 32 individuals 6months after hospitalization for bipolar depression showed a significant decrease in the levels of MPMV antibodies, but not a change in the other markers.
ConclusionIndividuals with acute bipolar depression show immune alterations. Some of the alterations are similar to those found in acute mania.
The effect of artemether on psychotic symptoms and cognitive impairment in first-episode, antipsychotic drug-naive persons with schizophrenia seropositive to Toxoplasma gondii
Wang, H. L., Xiang, Y. T., Li, Q. Y., Wang, X. P., Liu, Z. C., Hao, S. S., Liu, X., Liu, L. L., Wang, G. H., Wang, D. G., Zhang, P. A., Bao, A. Y., Chiu, H. F. K., Ungvari, G. S., Lai, K. Y. C., Buchanan, R. W.
Journal of Psychiatric Research 2014; 53: 119-124
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The objective was to evaluate the efficacy and safety of add-on artemether in first-episode, untreated people with schizophrenia, who were Toxoplasma gondii seropositive, and explore the change in T gondii antibodies during treatment. In this eight-week, double-blind, randomized, placebo-controlled trial, 100 T. gondii seropositive participants with schizophrenia were randomized to either the artemether or placebo group. Participants in the artemether group received 80 mg artemether once per day during the second week (days 8-14) and the fourth week (days 22-28). Participants in the placebo group received identical looking placebo capsules. Psychopathology, adverse side effects and cognitive function were measured using standardized instruments. The group x time interaction effects for the scores of the Positive and Negative Syndrome Scale (PANSS) subscales and performances on all cognitive components were not significant, only the main effect of group was significant. Compared to the placebo group, artemether group participants showed significantly greater reduction in the PANSS negative symptom scale (F-(1,F-46) = 4.7, p = 0.03) and the Clinical Global Impressions Scale (F-(1,F-96) = 6.2, p = 0.01) scores, but there were no significant differences in the PANSS positive symptom and general psychopathology scales (p > 0.05). There were also no significant differences between the two groups in performance on any of the Brief Assessment of Cognition in Schizophrenia (BACS) cognitive domains. The artemether risperidone combination is safe and well tolerated, but artemether as an adjunct to risperidone does not appear to alleviate cognitive deficits of schizophrenia. Trial Registration Chinese Clinical Trial Register (ChiCTR) TRC-13003145 (C) 2014 Elsevier Ltd. All rights reserved.
Inflammatory molecular signature associated with infectious agents in psychosis
Hayes, L. N., Severance, E. G., Leek, J. T., Gressitt, K. L., Rohleder, C., Coughlin, J. M., Leweke, F. M., Yolken, R. H., Sawa, A.
Schizophrenia Bulletin 2014; 40: 963-972
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Schizophrenia (SZ) is a devastating mental condition with onset in young adulthood. The identification of molecular biomarkers that reflect illness pathology is crucial. Recent evidence suggested immune and inflammatory cascades in conjunction with infection may play a role in the pathology. To address this question, we investigated molecular changes in cerebrospinal fluid (CSF) from antipsychoticnaive patients with SZ and at risk mental status for psychosis (ARMS), in comparison with healthy controls (HCs). We measured 90 analytes using a broad multiplex platform focusing on immune and inflammatory cascades then selected 35 with our quality reporting criteria for further analysis. We also examined Toxoplasma gondii (TG) and herpes simplex virus 1 antibody levels in CSF. We report that expression of 15 molecules was significantly altered in the patient groups (SZ and ARMS) compared with HCs. The majority of these molecular changes (alpha-2-macroglobulin [alpha 2M], fibrinogen, interleukin-6 receptor [IL-6R], stem cell factor [SCF], transforming growth factor alpha [TGF alpha], tumor necrosis factor receptor 2 [TNFR2], IL-8, monocyte chemotactic protein 2 [MCP-2/CCL8], testosterone [for males], angiotensin converting enzyme [ACE], and epidermal growth factor receptor) were consistent between SZ and ARMS patients, suggesting these may represent trait changes associated with psychotic conditions in general. Interestingly, many of these analytes (alpha 2M, fibrinogen, IL-6R, SCF, TGF alpha, TNFR2, IL-8, MCP-2/CCL8, and testosterone [for males]) were exacerbated in subjects with ARMS compared with subjects with SZ. Although further studies are needed, we optimistically propose that these molecules may be good candidates for predictive markers for psychosis from an early stage. Lastly, reduction of IL-6R, TGF alpha, and ACE was correlated with positivity of TG antibody in the CSF, suggesting possible involvement of TG infection in the pathology.
Toxoplasma gondii and other risk factors for schizophrenia: An update
Torrey, E.F., Bartko, J.J., Yolken, R.H.
Schizophrenia Bulletin 2012; 38: 642-647
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The failure to find genes of major effect in schizophrenia has refocused attention on nongenetic, including infectious factors. In a previous study, antibodies to Toxoplasma gondii were found to be elevated in 23 studies of schizophrenia (OR 2.73; 95% CI 2.10-3.60). The current study replicates this finding with 15 additional studies (OR 2.71; 95% CI 1.93-3.80) and compares this with other identified schizophrenia risk factors. The highest risk factors are having an affected mother (relative risks [RR] 9.31; 95% CI 7.24-11.96), father (RR 7.20; 95% CI 5.10-10.16), or sibling (RR 6.99; 95% CI 5.38-9.08) or being the offspring of immigrants from selected countries (RR 4.5; 95% CI 1.5-13.1). Intermediate risk factors, in addition to infection with T. gondii, include being an immigrant from and to selected countries (RR 2.7; 95% CI 2.3-3.2), being born in (RR 2.24; 95% CI 1.92-2.61) or raised in (RR 2.75; 95% CI 2.31-3.28) an urban area, cannabis use (OR 2.10-2.93; 95% CI 1.08-6.13), having minor physical anomalies (OR 2.23; 95% CI 1.42-3.58), or having a father 55 or older (OR 2.21-5.92; 95% CI 1.46-17.02). Low-risk factors include a history of traumatic brain injury (OR 1.65; 95% CI 1.17-2.32), sex abuse in childhood (OR 1.46; 95% CI 0.84-2.52), obstetrical complications (OR 1.29-1.38; 95% CI 1.00-1.84), having a father 45 or older (OR 1.21-1.66; 95% CI 1.09-2.01), specific genetic polymorphisms (OR 1.09-1.24; 95% CI 1.06-1.45), birth seasonality (OR 1.07-1.95; 95% CI 1.05-2.91), maternal exposure to influenza (RR 1.05; 95% CI 0.98-1.12), or prenatal stress (RR 0.98-1.00; 95% CI 0.85-1.16).
Toxoplasma infection in schizophrenia patients: A comparative study with control group
Alipour, A., Shojaee, S., Mohebali, M., Tehranidoost, M., Masoleh, F. A., Keshavarz, H.
Iranian Journal of Parasitology 2011; 6: 31-37
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Background: Schizophrenia is a serious, chronic, and often debilitating neuropsychiatric disorder. Its causes are still poorly understood. Besides genetic and non-genetic (environmental) factors are thought to be important as the cause of the structural and functional deficits that characterize schizophrenia. This study aimed to compare Toxoplasma gondii infection between schizophrenia patients and non-schizophrenia individuals as control group.
Methods: A case-control study was designed in Tehran, Iran during 2009-2010. Sixty-two patients with schizophrenia and 62 non-schizophrenia volunteers were selected. To ascertain a possible relationship between T. gondii infection and schizophrenia, anti-Toxoplasma IgG antibodies were detected by indirect-ELISA. Data were statistically analyzed by chi- square at a confidence level of 99%.
Results: The sero-positivity rate among patients with schizophrenia (67.7%) was significantly higher than control group (37.1) (P <0.01).
Conclusion: A significant correlation between Toxoplasma infection and schizophrenia might be expected.
The probable relation between Toxoplasma gondii and Parkinson’s disease
Miman, O., Kusbeci, O. Y., Aktepe, O. C., Cetinkaya, Z.
Neuroscience Letters 2010; 475: 129-131
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Parkinson's disease (PD), a chronic progressive neurodegenerative disorder, has a mainly unknown multifactorial etiology. Neuroinflammatory mechanisms might contribute to the cascade of events leading to neuronal degeneration. Toxoplasmosis can be associated with various neuropsychiatric disorders. The most commonly affected central nervous system (CNS) region in toxoplasmosis is the cerebral hemisphere, followed by the basal ganglia, cerebellum and brain stem. Therefore, in this study, we aimed to investigate the possible association between Toxoplasma infection and PD by evaluating the serum anti-Toxoplasma gondii IgG antibodies. There were no difference between the socioeconomic status of the patients and control subjects and magnetic resonance images of the patients were normal. Serum anti-T. gondii IgG levels were measured using ELISA. There was no statistically significant differences among the patients and control subjects with respect to age (66.01 +/- 12.14 years, 62.42 +/- 5.93 years, p = 0.089; respectively) and gender. The sero-positivity rate for anti-T. gondii IgG antibodies in PD patients and control groups were 42.3 and 22.5%, respectively, and they were statistically significant (p = 0.006). These results suggest that Toxoplasma infection may be involved in the pathogenetic mechanisms of PD. If confirmed, this hypothesis would represent a valuable advancement in care of patients with Parkinson's disease. (C) 2010 Elsevier Ireland Ltd. All rights reserved.
Schizophrenia and toxoplasmosis
Dion, S., Barbe, P. G., Leman, S., Camus, V., Dimier-Poisson, I.
M S-Medecine Sciences 2009; 25: 687-691.
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Schizophrenia and toxoplasmosis
Schizophrenia is one of the most severe and disabling psychiatric disease that affects about 1% of the adult worldwide population. Aetiology of schizophrenia is still unknown but genetic and environmental factors are suspected to play a major role in its onset. Recent epidemiologic studies indicate that infectious agents may contribute to some cases of schizophrenia. In particular, several epidemiological, behavioural and neurochemical studies suggested the existence of an association between schizophrenia and post history of primo-infection by the Toxoplasma gondii. However, they are some limitations for this hypothesis among which the lack of correlation between the geographic distribution of both diseases and of direct evidence for the presence of the parasite in schizophrenic patients. Nevertheless the identification of physiopathological mechanisms related to the parasite could provide a better comprehension to the outcome of schizophrenia. Studies on the link between toxoplasmosis and schizophrenic may provide interesting data for the diagnosis and the development of new treatments for this disorder.