Schizophrenia Bulletin Advance Access published November 9, 2014 Schizophrenia Bulletin doi:10.1093/schbul/sbu159
Meta-Analysis of Anti-Toxoplasma gondii IgM Antibodies in Acute Psychosis
1 Department of Psychiatry and Health Behavior, Georgia Regents University, Augusta, GA; 2Medical College of Georgia, Georgia Regents University, Augusta, GA
*To whom correspondence should be addressed; Department of Psychiatry and Health Behavior, Georgia Regents University, 997 Saint Sebastian Way, Augusta, GA 30912, US; tel: +1-706-721-4445, fax: +1-706-721-6602, e-mail: [email protected]
Introduction: A number of different infections are associated with acute psychosis. However, relationships between infections and acute psychosis in patients with schizophrenia have not been extensively explored. Exposure to Toxoplasma gondii is a replicated risk factor for schizophrenia. Previous studies have focused on T. gondii IgG antibodies, which are a marker of lifetime exposure, whereas IgM antibodies are a marker of acute/recent exposure, persistent infection, or reinfection. We performed a meta-analysis of T. gondii IgM antibodies and acute psychosis, to further investigate whether infections may be associated with relapse in schizophrenia. Methods: We identified articles by systematic searches of PubMed, PsycINFO, and ISI databases. We included studies, in English, of serum T. gondii IgM antibodies in patients with acute psychosis and controls. Results: Sixteen independent samples (2353 patients and 1707 controls) met inclusion criteria. Data were pooled using a random effects model. There was a significant increase in risk of positive T. gondii IgM antibodies in acute psychosis compared with controls (7.6% vs 5.7%, OR = 1.68, 95% CI = 1.23–2.27, P = .001). The association was stronger for patients with chronic schizophrenia (8.7% vs 4.6%, OR = 2.54, 95% CI = 1.63–3.96, P < .001) than first-episode psychosis. In meta-regression analyses, age, sex, and publication year were unrelated to the association; however, there was a significant association with geographic region. Discussion: An increased seroprevalence of T. gondii IgM in patients with acute psychosis complements and extends previous findings, suggesting that infections may be relevant to the etiopathophysiology of relapse in some patients with schizophrenia. Key words: infection/toxoplasmosis/psychosis/relapse/ meta-analysis Introduction Schizophrenia is associated with increased infections across the lifespan. Prenatal maternal infection, with a
variety of different infectious agents, is a replicated risk factor for schizophrenia1 and may act synergistically with family history of psychosis.2 Hospital contact for infection during childhood or adolescence is associated with an increased risk of schizophrenia.3 Schizophrenia is also associated with increased mortality from infectious diseases, including pneumonia and influenza.4,5 Outside of schizophrenia, a number of different viral, bacterial, and parasitic infections are associated with acute psychosis, a notable example being geriatric patients with psychosis and a comorbid urinary tract infection (UTI) in the context of either dementia or delirium.6,7 However, relationships between infections and acute psychosis in patients with schizophrenia have not been extensively explored. Acute psychosis is common and relapse prevention represents an important treatment issue in schizophrenia. Robinson et al8 found that 82% of patients with firstepisode psychosis (FEP) had an illness relapse within 5 years after recovery, and a majority had multiple relapses. Illness relapse is associated with adverse outcomes, including increased treatment-resistant symptoms, cognitive decline, and functional disability.9–11 Thus, to better understand and predict relapse in schizophrenia is a compelling opportunity and public health priority. Exposure to Toxoplasma gondii is a robust risk factor for schizophrenia. A meta-analysis found that subjects with FEP have a 2.5-fold increased risk of lifetime infection compared with controls, and a similar 2.7-fold increased risk of lifetime infection across all clinical phases of schizophrenia.12 Most previous studies have focused on T. gondii IgG antibodies, which are a marker of lifetime exposure to toxoplasmosis, whereas IgM antibodies are a marker of acute/recent infection,13 or also potentially persistent infection or reinfection, possibly with a different genotype.14–18 The objective of this study was to perform a meta-analysis of the association between T. gondii IgM antibodies and acute psychosis in schizophrenia, to further investigate whether infections may be associated
© The Author 2014. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For permissions, please email: [email protected]
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Joel M. Monroe1, Peter F. Buckley2, and Brian J. Miller*,1
J. M. Monroe et al
with relapse in schizophrenia. We hypothesize that there is an increased seroprevalence of T. gondii antibodies in patients with acute psychosis compared with controls. Methods Study Selection
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Data Extraction and Meta-Analysis Data were extracted for sample size and number of subjects seropositive for T. gondii IgM antibodies for acute psychosis and controls in each study. We also extracted descriptive data on geographic location, assay method, age, and sex. One author (B.J.M.) extracted all data, which was independently verified by another author (J.M.M.). Effect size estimates (ORs and 95% CIs) were aggregated utilizing the random effects method of DerSimonian and Laird.47 Random effects methods are considered to be more representative of real-world data in comparison to the alternative fixed effect approach48 and provide a more conservative estimate of the average weighted effect size.49 Random effects models also yield their actual first error rate while fixed effect models tend to inflate their first error rate. CIs obtained by fixed effect models are also biased and their actual coverage rate is smaller than their nominal coverage rate.50 Three studies that otherwise met the inclusion criteria could not be analyzed in the random effects meta-analysis because the prevalence of T. gondii IgM antibodies was zero for both acute psychosis and control groups, which results in an OR and 95% CI that is undefined.23,29,32 The main statistical hypothesis was that the ORs for the seroprevalence of T. gondii IgM in patients with acute psychosis vs controls equals 1.00. In a secondary analysis, we repeated the meta-analysis procedure for studies of FEP and chronic schizophrenia (each vs controls) considered separately. The meta-analysis procedure also calculates a χ2 value for the heterogeneity in effect size estimates, which is based on Cochran’s Q-statistic,51 and I2, the proportion of the variation in effect size attributable to between-study heterogeneity. Between-study heterogeneity χ2 was considered significant for P < .10.52 For all studies, and studies of chronic schizophrenia, between-study heterogeneity χ2 was significant, so we performed a sensitivity analysis. This was done by removing one study at a time and repeating the meta-analysis procedure, to examine its impact on the OR and between-study heterogeneity.53 Given
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Studies of T. gondii IgM antibodies in schizophrenia were systematically searched using Medline (PubMed, National Center for Biotechnology Information, US National Library of Medicine, Bethesda, MD), PsycINFO (via Ovid, American Psychological Association, Washington, DC), and Thomson Reuters (formerly ISI) Web of Knowledge (Science Citation Index and Social Sciences Citation Index, Thomson Reuters, Charlottesville, VA) from 1953 (when the first known study of T. gondii antibodies in patients with psychosis was published) through October 26, 2013, when the final search procedure was conducted. The primary search strategy was “(toxoplasma OR toxoplasmosis) AND (psychosis OR schizophrenia),” which yielded 160 articles from PubMed, 78 for PsycINFO, and 251 for ISI. Titles and abstracts of the resulting matches were screened for relevance to the present meta-analysis. The inclusion criteria were (1) case-control studies of serum T. gondii IgM antibodies in patients with acute psychosis in the context of schizophrenia or related psychotic spectrum disorders (including schizophreniform disorder, brief psychotic disorder, psychotic disorder not otherwise specified, delusional disorder, and schizoaffective disorder) and healthy controls, (2) the study had to be published, and (3) studies or abstracts had to be written in English. Patients with acute psychosis were further stratified by FEP or chronic schizophrenia. For studies that included patients with both FEP and chronic schizophrenia, if stratified data were not presented in the manuscript, we attempted to contact study authors. The exclusion criteria were: (1) studies that measured T. gondii IgG, but not IgM antibodies, (2) studies without a control group, (3) significant overlap in study population, (4) studies that assayed prenatal or antenatal samples, (5) studies of subjects at clinical high risk for psychosis, (6) studies of subjects with affective psychosis, and (7) review articles without primary data. For studies that measured both anti-T. gondii IgG and IgM antibodies, if stratified data were not presented in the manuscript, we attempted to contact study authors. From these sources, as well as a hand-searched review of reference lists, we identified 116 studies for potential inclusion. We did not employ formal search software and all publications were retrieved and examined in full text. Based on a preliminary review of these matches, 28 studies presented data on T. gondii IgM antibodies and warranted further consideration.19–46 These studies are summarized in table 1. The majority of initial matches were excluded because they did not present data on
T. gondii IgM antibodies or were review articles. After independent searches, detailed review of study methods by 2 authors (J.M.M. and B.J.M.) and attempts to contact study authors, 16 studies met the inclusion criteria, with 4 studies of FEP, 10 studies of chronic schizophrenia, and 2 studies of both FEP and chronic schizophrenia (15–30). Twelve studies were excluded from the final analysis due to: data on the prevalence of positive IgM antibodies not available (n = 5), uncertainty if patients were experiencing acute psychosis (n = 3), no control group (n = 2), patients not experiencing acute psychosis (n = 1), and significant overlap in study population (n = 1). There was universal agreement on the included studies. A flowchart summarizing the study selection process is presented in figure 1.
Meta-Analysis of Toxo IgM in Acute Psychosis
Table 1. Studies of Anti-Toxoplasma gondii IgM Antibodies in Schizophrenia IgM+ (n, %) Location
Status
Psychosis Control
Alvarado-Esquivel et al19 Alvarado-Esquivel et al20 Cetinkaya et al21 Daryani et al22 Dogruman-Al et al23 Hamidinejat et al24 Krause et al25 Liu et al26 Mahmoud and Hasan27 Tamer et al28 Yuksel et al29 Saraei-Sahnesaraei et al30 Hamidinejat et al24 James et al31
Mexico Mexico Turkey Iran Turkey Iran Germany China Iraq Turkey Turkey Iran Iran Nigeria
Chronic Chronic Chronic Chronic Chronic Chronic Chronic Chronic Chronic Chronic Chronic Chronic/FEP FEP FEP
3 7.9 2 4.0 1 1.0 30 37.5 0 0.0 2 3.4 1 3.2 49 10.3 2 2.1 2 5.0 0 0.0 15 14.4 2 5.0 10 7.1
Tanyuksel et al32 Wang et al33 Yolken et al34
Turkey China Germany
FEP FEP FEP
0 0.0 32 5.3 5 13.2
Total—included Bachmann et al35 Dickerson et al36
Not specified United States
156 FEP 34 Chronic/FEP 302
Dickerson et al37
United States
Chronic/FEP
Hinze-Selch et al38
Germany
Chronic
Hinze-Selch et al39
Germany
6.6
Mean Age Comment/Assay (Years) Male (%) Included Method
4 2.2 42.7 0 0.0 45.1 0 0.0 37.2 36 36.4 33.4 0 0.0 33.9 2 4.2 33.0 0 0.0 35.2 0 0.0 29.3 0 0.0 38.3 1 2.7 33.0 0 0.0 42.6 23 20.2 2 4.2 12 8.6 28.7 0 5 1 86
0.0 25.8 2.5 22.6 3.7 27.0 5.0
70.3 80.0 49.3 56.3 59.0 51.8 53.1 39.6 60.0
Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes
91.2 47.0
Yes Yes Yes
207
25.5 35.4
47.1 51.3
No No
314
34.6
51.8
No
344
214
38.3
43.6
No
Chronic
277
214
37.4
Holub et al40 Juanah et al41
Czech Republic Chronic Malaysia Unclear
0 1
Leweke et al42
Not specified
Multiple
Ling et al43
China
FEP
Nascimento et al44
Brazil
Outpatients
Niebuhr et al45
United States
Yonghua et al46
China
0.0 1.1
0 1
75
73
600
400
41
95
Unclear
180
532
Unclear
107
6.2
82
No
0.0 1.1
No No 29.8
77.3
No No
36.5
5.3
55.1
No
83.7
No No
ELISA ELISA ELISA ELISA ELISA ELISA ELISA ELISA ELISA ELISA ELISA ELISA ELISA Chromatographic immunoassay ELISA ELISA Immunoblot analysis No control group Data on IgM+ not available Data on IgM+ not available Data on IgM+ not available Study population overlap No control group Clinical status unclear Data on IgM+ not available Data on IgM+ not available No acute psychosis Clinical status unclear Clinical status unclear
Note: ELISA, enzyme-linked immunosorbent assay; FEP, first-episode psychosis.
the significant heterogeneity in the overall result, we also performed a series of meta-regressions to explore possible moderating variables to account for such heterogeneity. Meta-regression assesses and adjusts the effects of potential moderating variables on the effect size estimate from the meta-analysis (much in the same way that regression assesses the relationships between moderating variables and a dependent variable). A positive slope (ie, regression coefficient) means that the effect size estimate from the meta-analysis and the moderator variable change in the same direction, and a negative slope means they change in the opposite
direction. We conducted meta-regression analyses of age, sex, geographic location (latitude and longitude, considered separately, as well as region), and year of publication. As 14 of the 16 studies measured T. gondii IgM using enzyme-linked immunosorbent assay, we did not perform a meta-regression with assay method. Potential for publication bias was examined by means of Sterne’s funnel plot analysis54 and Egger’s regression intercept.55 The statistical analyses were performed in Stata 10.0 (StataCorp LP).56 All tests were 2-sided, and P values were considered statistically significant at the α = .05 level. Page 3 of 10
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Study
J. M. Monroe et al
Search Strategy: "(toxoplasma OR toxoplasmosis) AND (psychosis OR schizophrenia)” 3 databases searched: Medline PsycInfo Thomson Reuters Web of Knowledge Plus manual review of reference lists.
(n=160) (n=78) (n=251)
N=90 excluded, most commonly due to:
1) Measured anti-Toxoplasma gondii IgG, but not IgM 2) Review articles
N=28 Studies with data on anti-Toxoplasma gondii IgM Antibodies warranting further review
N=12 excluded: n=5 n=3 n=2 n=1 n=1
Data on the prevalence of IgM+ not available Unclear if patients experiencing acute psychosis No control group Patients not experiencing acute psychosis Significant study population overlap
N=16 Studies included in the meta-analysis n=4 n=10 n=2
First-episode psychosis (FEP) Chronic schizophrenia FEP and chronic schizophrenia
Fig. 1. Flowchart of the study selection process.
Results As described in table 1, search procedures yielded 16 independent studies, comprising 2353 patients with acute psychosis (including 818 subjects with FEP) and 1707 controls for inclusion in the meta-analysis. In all studies, there was a significant increase in risk of seropositive T. gondii IgM antibodies in acute psychosis compared with controls (7.6% vs 5.7%, OR = 1.68, 95% CI = 1.23– 2.27, P = .001). There was significant heterogeneity in this estimate (χ2 = 22.05, P = .055; I2 = 41.1%). In a sensitivity analysis, the heterogeneity remained significant after removal of each individual study. However, after removing the 2 studies with the highest seroprevalence of positive IgM antibodies in controls,22,30 the association was notably stronger (6.1% vs 2.4%, OR = 2.81, 95% CI = 1.80–4.37, P < .001) and the heterogeneity was no longer statistically significant (χ2 = 15.82, P = .148; I2 = 30.5%). In studies of acute psychosis in the context of chronic schizophrenia, the association with T. gondii IgM antibodies was stronger (8.7% vs 4.6%, OR = 2.54, 95% CI = 1.63–3.96, P < .001), but there was significant Page 4 of 10
heterogeneity in this estimate (χ2 = 15.52, P = .050; I2 = 48.5%). In a sensitivity analysis, the association was notably stronger (6.5% vs 0.9%, OR = 6.89, 95% CI = 3.10– 15.34, P < .001) and the heterogeneity was no longer statistically significant (χ2 = 9.30, P = .232; I2 = 24.8%) after excluding one study.22 In studies of FEP, there was a nonsignificant increase in T. gondii IgM antibodies compared with controls (5.7% vs 4.6%, OR = 1.47, 95% CI = 0.84–2.58, P = .181) and the heterogeneity was not significant (χ2 = 3.19, P = .363; I2 = 5.9%). Forest plots for the meta-analyses are presented as figure 2. A funnel plot display for data derived from all studies included in the meta-analysis (figure 2) and results of Egger’s test (intercept = 1.04, 95% CI = −0.33 to 2.41, P = .118) showed no evidence for potential publication bias. In meta-regression analyses, age, sex, latitude and longitude, and year of publication were all unrelated to the association between T. gondii IgM antibodies and acute psychosis (P > .05 for each), meaning they were not associated with T. gondii IgM seropositivity. However, there was a significant association with geographic region
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N=118 Potential studies for meta-analysis
Meta-Analysis of Toxo IgM in Acute Psychosis
2a. All studies
2b. Chronic Schizophrenia
%
Study ID
OR (95% CI)
W eight
Alvarado-Esquivel 2006
3.77 (0.81, 17.60)
1.92
Alvarado-Esquivel 2011
15.52 (0.73, 328.78)
0.36
Cetinkaya 2007
1.52 (0.06, 38.05)
0.98
Daryani 2010
1.05 (0.57, 1.93)
30.13
Hamidinejat 2010
0.82 (0.11, 6.06)
Krause 2010
%
Study ID
OR (95% CI)
Weight
3.77 (0.81, 17.60)
4.76
15.52 (0.73, 328.78)
0.89
3.17
Cetinkaya 2007
1.52 (0.06, 38.05)
2.43
3.00 (0.12, 76.58)
0.73
Daryani 2010
1.05 (0.57, 1.93)
74.53
Liu 2011
48.63 (2.99, 792.32)
0.93
Hamidinejat 2010
0.82 (0.11, 6.06)
7.83
Krause 2010
3.00 (0.12, 76.58)
1.79
Liu 2011
48.63 (2.99, 792.32)
2.30
Mahmoud 2009
5.11 (0.24, 107.77)
1.81
Tamer 2008
1.89 (0.16, 21.81)
3.66
Dogruman-Al 2009
(Excluded)
0.00
Yuksel 2010
(Excluded)
0.00
Overall (I-squared = 48.5%, p = 0.050)
2.54 (1.63, 3.96)
100.00
Mahmoud 2009
5.11 (0.24, 107.77)
0.73
Tamer 2008
1.89 (0.16, 21.81)
1.48
Saraei-Sahnesaraei 2009
0.67 (0.33, 1.36)
28.13
Hamidinejat 2010
1.21 (0.16, 9.00)
2.59
James 2013
0.82 (0.34, 1.97)
16.69
W ang 2006
2.20 (0.84, 5.72)
10.64
Yolken 2001
3.94 (0.43, 35.83)
1.52
Dogruman-Al 2009
(Excluded)
0.00
Yuksel 2010
(Excluded)
0.00
Tanyuksel 2010
(Excluded)
0.00
Overall (I-squared = 41.1%, p = 0.055)
1.68 (1.23, 2.27)
100.00
.1
1
.1
10
2c. First-Episode Psychosis
1
10
2d. Funnel Plot for All Studies
Anti-Toxoplasma gondii IgM Ab Funnel plot with pseudo 95% confidence limits
%
0
Study
OR (95% CI)
Weight
Hamidinejat 2010
1.21 (0.16, 9.00)
8.23
James 2013
0.82 (0.34, 1.97)
53.10
Wang 2006
2.20 (0.84, 5.72)
33.83
Yolken 2001
3.94 (0.43, 35.83)
4.84
Tanyuksel 2010
(Excluded)
0.00
Overall (I-squared = 5.9%, p = 0.363)
1.47 (0.84, 2.58)
100.00
1.5
1
.5
ID
.1
1
10
logor
5
10
15
Fig. 2. Meta-analysis of Anti-Toxoplasma gondii IgM antibodies.
(slope = −0.41, 95% CI = −0.80 to −0.01, P = .044), with a stronger association in studies from Asia, Europe, and South America (regions with a lower prevalence of T. gondii IgM positive controls), than in studies from Africa and the Middle East (figure 3). Discussion The present study consisted of a meta-analytic review of the association between T. gondii IgM antibodies and acute psychosis in patients with schizophrenia and healthy controls. We found a significant, 1.7-fold increased risk of T. gondii IgM antibodies in subjects with acute psychosis, of whom 7.6% were seropositive. This association was not moderated by age, sex, or year of publication. However, the association was moderated by geographic
region, with greater effect sizes in studies from Asia, Europe, and South America. An important strength of our study is that we considered T. gondii IgM antibodies, whereas previous studies have focused primarily on T. gondii IgG antibodies, which are a marker of lifetime exposure to toxoplasmosis.12 T. gondii IgM antibodies could represent either an acute/ recent infection,13 or also potentially persistent infection or reinfection, possibly with a different genotype.14–18 Thus, our work complements and extends previous findings, raising the possibility that exposure to T. gondii is not only an important risk factor for schizophrenia, but may also be associated with relapse in schizophrenia. Another strength of the present study is that we performed meta-regression analyses to consider moderating effects of age, sex, geography, and publication year. Page 5 of 10
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Alvarado-Esquivel 2006 Alvarado-Esquivel 2011
-.5 1
Geographic Region 1 2 3 4 5
South America Asia Europe Middle East Africa
2
3 geography
Studies (n) 2 2 2 9 1
4
5
% IgM+ Schizophrenia Control 5.7 1.2 7.5 1.2 8.7 1.8 5.5 8.3 7.1 8.6
Fig. 3. Meta-regression analysis of the effects of geographic region on the association between anti-Toxoplasma gondii IgM and acute psychosis.
Previous studies have found a prevalence of T. gondii IgM antibodies of 0.3% in healthy blood donors from Taiwan,57 1.6% in Italian women of childbearing age,58 2.1% in a general population sample in Mexico,59 2.4% among blood donors from the Czech Republic,60 and 4.6% among healthy volunteers in Nigeria,61 all of which are lower than the 5.7% prevalence in controls included in this meta-analysis, which raises the possibility of selection bias. However, the higher prevalence of T. gondii IgM antibodies in our controls would bias the OR toward the null hypothesis of no association with acute psychosis. Furthermore, the 2 studies removed in the sensitivity analysis also had the highest prevalence of subjects (both patients and controls) with T. gondii IgM antibodies. When these 2 studies were removed, the prevalence of T. gondii IgM antibodies in controls decreased to 2.4%, which is comparable with other general population studies cited above. Thus, although this approach could increase the OR by decreasing the prevalence of T. gondii IgM antibodies in controls, the statistical significance in both analyses points to an association that is not the result of bias. In a post-hoc analysis, we considered the effect of dropping the 3 studies where no subjects had positive T. gondii IgM antibodies. We calculated the prevalence of positive T. gondii IgM antibodies, using absolute numbers rather than calculating ORs and 95% CIs for individual studies, with these 3 studies included. We then calculated an overall OR and 95% CI for the prevalence of positive T. gondii IgM in patients with acute psychosis vs controls. In all studies, the significant increase in risk of seropositive Page 6 of 10
T. gondii IgM antibodies in acute psychosis compared with controls remained (6.6% vs 5.0%, OR = 1.34, 95% CI = 1.02–1.75, P = .035). Furthermore, in studies of acute psychosis in the context of chronic schizophrenia, the significant association with T. gondii IgM antibodies also remained (6.8% vs 3.8%, OR = 1.85, 95% CI = 1.28–2.68, P = .001). We also note that all 3 studies with no positive T. gondii IgM subjects were from Turkey. Two other included studies from Turkey had a very low prevalence of positive T. gondii IgM in patients (2.1%, 3 of 140) and controls (1.1%, 1 of 87), suggesting a regionspecific effect. These findings support the robustness of the overall association. We also performed subgroup analyses, comparing chronic schizophrenia and FEP separately. We found a significant association between acute psychosis and acute/recent toxoplasmosis in chronic schizophrenia, but a nonsignificantly increased risk in FEP. One possible explanation for this finding is that our study lacked sufficient statistical power to detect an association in FEP, as the sample size for FEP was approximately half that for chronic schizophrenia. Post-hoc calculations revealed that a total sample of 4078 subjects (2039 patients and controls) would be required to have 80% power to detect a minimum OR of 1.47, assuming a 4.6% prevalence of positive T. gondii IgM in controls. Alternatively, it is possible that the association with T. gondii IgM exists for relapse of chronic schizophrenia, but not FEP. Although the association was not moderated by age, it is possible that subjects with a longer duration of psychotic illness could have greater exposure to infectious agents than subjects with FEP due to illness-related factors. There are several limitations of the present study. Only a subset of published studies on T. gondii and schizophrenia met the inclusion criteria. Many excluded studies measured T. gondii IgG, but not IgM antibodies. Included studies may have used different assay methodologies and “cut-off points” for determining IgM positivity, but corresponding data were not presented. Data on the IgG status of patients seropositive for IgM antibodies were generally not available, which could inform on whether IgM positivity represents acute/recent infection, persistent infection, or reactivation of a latent infection. Data were also not available to confirm whether subjects with positive T. gondii IgM antibodies had clinical signs and/or symptoms of acute infection. Several other studies that measured IgM antibodies were excluded because data were not reported as the prevalence of IgM-positive subjects. Although our findings are subject to a potential selection bias, we attempted to mitigate this effect by contacting study authors to either clarify information or to request summary data to facilitate comparison with other studies. Another limitation is that we were not able to control for other potential confounding factors such as the uniformity of diagnoses across studies, definitions of relapse and first episode, duration of illness, number of
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0
logor .5
1
1.5
J. M. Monroe et al
Meta-Analysis of Toxo IgM in Acute Psychosis
infection (including cytomegalovirus, herpes simplex virus type 1, mumps, measles, and Japanese encephalitis virus) in parallel with their clinical syndrome, based on diagnostic (ie, 4-fold) changes in paired antibody titers. Fellerhoff et al68 found a 9.4-fold increased risk of chlamydial infection in 72 patients hospitalized for schizophrenia compared with 225 controls (40.3% vs 6.7%). Ahokas et al.69 found that 37% of 54 acutely ill psychiatric patients had evidence of viral infection in parallel with acute psychiatric symptoms, also based on diagnostic changes in paired antibody titers. Although diagnosis information was not available for this study, it is reasonable to assume many of these patients were experiencing acute psychosis. Krause et al25 found a 9.7% prevalence of cytomegalovirus IgM antibodies among 31 inpatients with schizophrenia, vs 0% in 30 healthy controls. Given associations between different infectious exposures, these findings suggest that a rigorously designed longitudinal study is warranted to investigate issues of causality and temporality regarding associations with acute psychosis. The association between T. gondii IgM and acute psychosis also warrants replication in other samples from diverse geographic regions. Most importantly, in order to further understand and clarify the biological relevance of this association, longitudinal studies are needed, with serial measurement of both anti-T. gondii IgM and IgG antibody titers in relation to the clinical course of schizophrenia. Future studies should investigate this association in stable outpatients with schizophrenia, to evaluate whether it is more specific to episodes of illness relapse or schizophrenia in general. Replicated findings in well-controlled studies would suggest adjunctive treatment with antitoxoplasmosis agents might be a novel therapeutic strategy in antibody-positive patients. Given that several different acute infections may be increased in patients with acute psychosis in the context of schizophrenia, this association could also be explored with other common infections, such as cellulitis and pneumonia. Taken together, acute/recent infections appear increasingly relevant to the psychotic relapse in some patients with schizophrenia. Funding In the past 3 years, Dr B.J.M. has received grant support from the National Institute of Mental Health (K23MH098014) and Georgia Regents University, and research support from the National Institutes of Health Clinical Loan Repayment Program. Acknowledgments The authors wish to thank Drs Faith Dickerson, Cosme Alvarado-Esquivel, Bawo James, Bekir Kocazeybek, and Zhao-Rong Lun for sharing data and/or articles. The Page 7 of 10
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lifetime episodes of acute psychosis (and whether or not prior episodes were associated with T. gondii), the duration of clinical stability prior to acute psychosis, exposure to cats, consumption of raw or undercooked meats, and antipsychotic medications. The impact of these factors on the association remains unclear. Although the association was moderated by geographic region, 9 of the 16 studies (56%) were performed in the Middle East, with no more than 2 studies in any other geographic region, including no studies in North America. Both geography62 and latitude63 may be associated with seroprevalence of T. gondii. Latitudinal variability may be due to local rainy conditions (oocysts live longer in more humid conditions) and low altitude regions. Factors contributing to geographic variability may include exposure to cats and/ or consumption of raw or undercooked meat. There is also evidence for different T. gondii serotypes based on geography, including serotype II in Europe and of serotypes I and III in South America.64 It is not clear whether this association is specific to acute psychosis or to schizophrenia in general. We identified only one study that measured T. gondii IgM antibodies in stable patients with schizophrenia,44 but the prevalence of positive antibodies was zero in both patient and control groups. While this finding could support an association that is specific to acute psychosis, it may also be due to a relatively small sample size, selection factors, or geographic factors. In addition, data on the seroprevalence of other comorbid infections, and factors that may have provoked the onset of acute psychosis, would permit a more comprehensive assessment of the potential for confounding and of other infections on these relapses. Our study also does not permit inferences regarding either temporal or causal aspects of this association. IgM antibodies can remain positive for months to 2 years after acute toxoplasmosis, and can also reemerge following reactivation of latent infection; thus, the timing of exposure relative to the episode of acute psychosis is unclear. One possibility is that acute psychosis, and the concurrent stress, could either increase vulnerability to exposure to toxoplasmosis (eg, a patient with disorganized behavior might be more likely to consume raw or undercooked meat), or cause a reactivation of latent infection. By contrast, it is possible that T. gondii infection precedes acute psychosis. A previous meta-analysis found an increased risk of T. gondii IgG antibodies in schizophrenia, suggesting that exposure often precedes illness onset.12 Several other studies have reported associations between acute/recent infections and acute psychosis. We have replicated an association between UTI and acute psychosis in patients with schizophrenia.65,66 In one of these studies, there was a significant association with UTI among acutely ill inpatients, but not stable outpatients with schizophrenia compared with controls.65 Srikanth et al67 found that 29% of 35 patients with acute psychosis had a definite, ongoing viral
J. M. Monroe et al
References 1. Brown AS, Derkits EJ. Prenatal infection and schizophrenia: a review of epidemiologic and translational studies. Am J Psychiatry. 2010;167:261–280. 2. Clarke MC, Tanskanen A, Huttunen M, Whittaker JC, Cannon M. Evidence for an interaction between familial liability and prenatal exposure to infection in the causation of schizophrenia. Am J Psychiatry. 2009;166:1025–1030. 3. Nielsen PR, Benros ME, Mortensen PB. Hospital contacts with infection and risk of schizophrenia: a populationbased cohort study with linkage of danish national registers. Schizophr Bull. 2014;40:1526–1532. 4. Saha S, Chant D, McGrath J. A systematic review of mortality in schizophrenia: is the differential mortality gap worsening over time? Arch Gen Psychiatry. 2007;64:1123–1131. 5. Brown S, Kim M, Mitchell C, Inskip H. Twenty-five year mortality of a community cohort with schizophrenia. Br J Psychiatry. 2010;196:116–121. 6. Brendel RW, Stern TA. Psychotic symptoms in the elderly. Prim Care Companion J Clin Psychiatry. 2005;7:238–241. 7. Webster J, Grossberg GT. Late-life onset of psychotic symptoms. Am J Geriatr Psychiatry. 1998;6:196–202. 8. Robinson D, Woerner MG, Alvir JM, et al. Predictors of relapse following response from a first episode of schizophrenia or schizoaffective disorder. Arch Gen Psychiatry. 1999;56:241–247. 9. Müller N, Riedel M, Scheppach C, et al. Beneficial antipsychotic effects of celecoxib add-on therapy compared to risperidone alone in schizophrenia. Am J Psychiatry. 2002;159:1029–1034. 10. Shepherd M, Watt D, Falloon I, Smeeton N. The natural history of schizophrenia: a five-year follow-up study of outcome and prediction in a representative sample of schizophrenics. Psychol Med Monogr Suppl. 1989;15:1–46. 11. Wyatt RJ. Early intervention with neuroleptics may decrease the long-term morbidity of schizophrenia. Schizophr Res. 1991;5:201–202. 12. Torrey EF, Bartko JJ, Lun ZR, Yolken RH. Antibodies to Toxoplasma gondii in patients with schizophrenia: a metaanalysis. Schizophr Bull. 2007;33:729–736. 13. 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.
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14. Duffy KT, Wharton PJ, Johnson JD, New L, Holliman RE. Assessment of immunoglobulin-M immunosorbent agglutination assay (ISAGA) for detecting toxoplasma specific IgM. J Clin Pathol. 1989;42:1291–1295. 15. Dzitko K, Staczek P, Gatkowska J, Dlugonska H. Toxoplasma gondii: serological recognition of reinfection. Exp Parasitol. 2006;112:134–137. 16. Giraldo M, Portela RW, Snege M, et al. Immunoglobulin M (IgM)-glycoinositolphospholipid enzyme-linked immunosorbent assay: an immunoenzymatic assay for discrimination between patients with acute toxoplasmosis and those with persistent parasite-specific IgM antibodies. J Clin Microbiol. 2002;40:1400–1405. 17. Hassan M, Hegab M, Abaza BE, Nasr ME, Mowafy NM. Specific anti-Toxoplasma antibodies in relation to infection and reinfection using different infective stages. J Egypt Soc Parasitol. 1999;29:119–129. 18. Sharma SD, Mullenax J, Araujo FG, Erlich HA, Remington JS. Western blot analysis of the antigens of Toxoplasma gondii recognized by human IgM and IgG antibodies. J Immunol. 1983;131:977–983. 19. Alvarado-Esquivel C, Alanis-Quiñones OP, ArreolaValenzuela MA, et al. Seroepidemiology of Toxoplasma gondii infection in psychiatric inpatients in a northern Mexican city. BMC Infect Dis. 2006;6:178–184. 20. Alvarado-Esquivel C, Urbina-Álvarez JD, Estrada-Martínez S, et al. Toxoplasma gondii infection and schizophrenia: a case control study in a low Toxoplasma seroprevalence Mexican population. Parasitol Int. 2011;60:151–155. 21. Cetinkaya Z, Yazar S, Gecici O, Namli MN. Anti-Toxoplasma gondii antibodies in patients with schizophrenia–preliminary findings in a Turkish sample. Schizophr Bull. 2007;33:789–791. 22. Daryani A, Mehdi S, Sayed HH, Sayed AK, Shirzad G: Serological survey of Toxoplasma gondii in schizophrenia patients referred to Psychiatric Hospital, Sari City, Iran. Trop Biomed. 2010;27:476–482. 23. Dogruman-Al F, Aslan S, Yalcin S, Kustimu S, Turk S. A possible relationship between Toxoplasma gondii and schizophrenia: a seroprevalence study. Int J Psychiatr Clin Pract. 2009;13:82–87. 24. Hamidinejat H, Ghorbanpoor M, Hosseini H, et al. Toxoplasma gondii infection in first-episode and inpatient individuals with schizophrenia. Int J Infect Dis. 2010;14:e978–e981. 25. Krause D, Matz J, Weidinger E, et al. The association of infectious agents and schizophrenia. World J Biol Psychiatry. 2010;11:739–743. 26. Liu M, Want T, Li H, et al. Analysis of the antibodies anti-Toxoplasma gondii by ELISA based on two diagnostic antigens: rSAG1 and rBAG1. Acta Parasitologica. 2011;56:353–359. 27. Mahmoud SS, Hasan MS: Seroprevalence of toxoplasmosis among Schizophrenic patients. Yemeni J Med Sci. 2009;1:1–7. 28. Tamer GS, Dundar D, Yalug I, Caliskan S, Yazar S, Aker A. The schizophrenia and Toxoplasma gondii connection: infectious, immune or both? Adv Ther. 2008;25:703–709. 29. Yuksel P, Alpay N, Babur C, et al. The role of latent toxoplasmosis in the aetiopathogenesis of schizophrenia–the risk factor or an indication of a contact with cat? Folia Parasitol (Praha). 2010;57:121–128. 30. Saraei-Sahnesaraei MS, Shamloo F, Hashemi HJ, Khabbaz F, Alizadeh S-A. Relation between Toxoplasma gondii
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authors also wish to thank Niju Philip for assistance with manuscript preparation and Billy Houke for assistance with references. Contributors: Dr B.J.M. designed the study. Drs B.J.M. and J.M.M. managed the literature searches and the analyses. Drs P.F.B., B.J.M., and J.M.M. wrote the first draft of the manuscript. All authors contributed to and have approved the final manuscript. Dr J.M.M. has nothing to disclose. Dr P.F.B. is a consultant (Honorarium/Expenses) for the National Institute of Mental Health. B.J.M. has nothing to disclose for this work. In the past three years, Dr B.J.M. has received consultancy fees for surveys from Medefied Europe and MDLinx.com, and speaker fees for grand rounds lectures from Emory University and the Zucker-Hillside Hospital.
Meta-Analysis of Toxo IgM in Acute Psychosis
2007 in Suzhou and Wuxi regions, Jiangsu, China. Trop Med Int Health. 2011;16:367. 47. DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials. 1986;7:177–188. 48. National Research Council. Combining Information: Statistical Issues and Opportunities for Research. Washington, DC: National Academy Press; 1992. 49. Field AP. Meta-analysis of correlation coefficients: a Monte Carlo comparison of fixed- and random-effects methods. Psychol Methods. 2001;6:161–180. 50. Hunter J, Schmidt F. Fixed effects vs. random effects metaanalysis models: implications for cumulative research knowledge. Int J Selection Assess. 2000;8:275–292. 51. Cochran WB. The comparison of percentages in matched samples. Biometrika. 1950;37:256–266. 52. Song F, Sheldon TA, Sutton AJ, Abrams KR, Jones DR. Methods for exploring heterogeneity in meta-analysis. Eval Health Prof. 2001;24:126–151. 53. Higgins JPT, Green S. Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 [updated March 2011]. 9.7. Sensitivity analyses. The Cochrane Collaboration, 2011. www.cochrane-handbook.org. 54. Sterne JAC, Egger M. Funnel plots for detecting bias in meta-analysis: guidelines on choice of axis. J Clin Epidemiol. 2001;54:1046–1055. 55. Egger M, Davey Smith G, Schneider M, Minder C. Bias in meta-analysis detected by a simple, graphical test. Br Med J. 1997;315:629–634. 56. StataCorp. Stata Statistical Software: Release 10. College Station, TX: StataCorp LP; 2007. 57. Chiang TY, Hsieh HH, Kuo MC, et al. Seroepidemiology of Toxoplasma gondii infection among healthy blood donors in Taiwan. PLoS One. 2012;7:e48139. 58. Mosti M, Pinto B, Giromella A, et al. A 4-year evaluation of toxoplasmosis seroprevalence in the general population and in women of reproductive age in central Italy. Epidemiol Infect. 2013;141:2192–2195. 59. Alvarado-Esquivel C, Estrada-Martínez S, Pizarro-Villalobos H, Arce-Quiñones M, Liesenfeld O, Dubey JP. Seroepidemiology of Toxoplasma gondii infection in general population in a northern Mexican city. J Parasitol. 2011;97:40–43. 60. Svobodová V, Literák I. Prevalence of IgM and IgG antibodies to Toxoplasma gondii in blood donors in the Czech Republic. Eur J Epidemiol. 1998;14:803–805. 61. Ogoina D, Onyemelukwe GC, Musa BO, Obiako RO. Seroprevalence of IgM and IgG antibodies to Toxoplasma infection in healthy and HIV-positive adults from Northern Nigeria. J Infect Dev Ctries. 2013;7:398–403. 62. Moncada PA, Montoya JG. Toxoplasmosis in the fetus and newborn: an update on prevalence, diagnosis and treatment. Expert Rev Anti Infect Ther. 2012;10:815–828. 63. Flegr J, Prandota J, Sovičková M, Israili ZH. Toxoplasmosis–a global threat. Correlation of latent toxoplasmosis with specific disease burden in a set of 88 countries. PLoS One. 2014;9:e90203. 64. Morisset S, Peyron F, Lobry JR, et al. Serotyping of Toxoplasma gondii: striking homogeneous pattern between symptomatic and asymptomatic infections within Europe and South America. Microbes Infect. 2008;10:742–747. 65. Miller BJ, Graham KL, Bodenheimer CM, Culpepper NH, Waller JL, Buckley PF. A prevalence study of urinary tract infections in acute relapse of schizophrenia. J Clin Psychiatry. 2013;74:271–277.
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infections and schizophrenia. Iranian J Psychiatr Clin Psychol. 2009;15:3–9. 31. James BO, Agbonile IO, Okolo M, Lawani AO, Omoaregba JO. Prevalence of Toxoplasma gondii infection among individuals with severe mental illness in Nigeria: a case control study. Pathog Glob Health. 2013;107:189–193. 32. Tanyuksel M, Uzun O, Araz E, Koru O, Babur C. Possible role of toxoplasmosis in patients with first-episode schizophrenia. Turk J Med Sci. 2010;40:399–404. 33. Wang HL, Wang GH, Li QY, Shu C, Jiang MS, Guo Y. Prevalence of Toxoplasma infection in first-episode schizophrenia and comparison between Toxoplasma-seropositive and Toxoplasma-seronegative schizophrenia. Acta Psychiatr Scand. 2006;114:40–48. 34. Yolken RH, Bachmann S, Ruslanova I, et al. Antibodies to Toxoplasma gondii in individuals with first-episode schizophrenia. Clin Infect Dis. 2001;32:842–844. 35. Bachmann S, Schröder J, Bottmer C, Torrey EF, Yolken RH. Psychopathology in first-episode schizophrenia and antibodies to Toxoplasma gondii. Psychopathology. 2005;38:87–90. 36. Dickerson F, Stallings C, Origoni A, et al. A combined marker of inflammation in individuals with mania. PLoS One. 2013;8:e73520. 37. Dickerson F, Stallings C, Origoni A, et al. Antibodies to Toxoplasma gondii in individuals with mania. Bipolar Disorders. 2014;16:129–136. 38. Hinze-Selch D, Däubener W, Erdag S, Wilms S: The diagnosis of personality disorder increases the likelihood of seropositivity to Toxoplasma gondii in psychiatric patients. Folia Parasitologica. 2010;57:129–135. 39. Hinze-Selch D, Däubener W, Eggert L, Erdag S, Stoltenberg R, Wilms S. A controlled prospective study of Toxoplasma gondii infection in individuals with schizophrenia: beyond seroprevalence. Schizophr Bull. 2007;33:782–788. 40. Holub D, Flegr J, Dragomirecká E, et al. Differences in onset of disease and severity of psychopathology between toxoplasmosis-related and toxoplasmosis-unrelated schizophrenia. Acta Psychiatr Scand. 2013;127:227–238. 41. Juanah LY, Jalaludin J, Osman M, Osman ZJ: Seroprevalence of Toxoplasma gondii among schizophrenics at Hospital Kajang. Am J Infect Diseases. 2013;9:11–16. 42. 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. 43. Ling WH, Wang GH, Li QY, Shu C, Jiang MS, Guo Y. Prevalence of toxoplasma infection in first-episode schizophrenia and comparison between toxoplasma-positive and toxoplasma-negative schizophrenia. Schizophr Bull. 2005;31: 203–204. 44. Nascimento FS, de Rosalmeida Dantas C, Netto MP, et al. Prevalence of antibodies to Toxoplasma gondii in patients with schizophrenia and mood disorders. Schizophr Res. 2012;142:244–245. 45. Niebuhr DW, Millikan AM, Cowan DN, Yolken R, Li Y, Weber NS. Selected infectious agents and risk of schizophrenia among U.S. military personnel. Am J Psychiatry. 2008;165:99–106. 46. Yonghua Z, Yue C, Lei Z, Qi G: Analysis of probable correlation between Toxoplasma gondii and schizophrenia: a seroepidemiological longitudinal investigation from 2002 to
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66. Graham KL, Carson CM, Ezeoke A, Buckley PF, Miller BJ. Urinary tract infections in acute psychosis. J Clin Psychiatry. 2014;75:379–385. 67. Srikanth S, Ravi V, Poornima KS, Shetty KT, Gangadhar BN, Janakiramaiah N. Viral antibodies in recent onset, nonorganic psychoses: correspondence with symptomatic severity. Biol Psychiatry. 1994;36:517–521.
68. Fellerhoff B, Laumbacher B, Mueller N, Gu S, Wank R. Associations between Chlamydophila infections, schizophrenia and risk of HLA-A10. Mol Psychiatry. 2007;12:264–272. 69. Ahokas A, Rimón R, Koskiniemi M, Vaheri A, Julkunen I, Sarna S. Viral antibodies and interferon in acute psychiatric disorders. J Clin Psychiatry. 1987;48:194–196.
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Meta-Analysis of Anti-Toxoplasma gondii IgM Antibodies in Acute Psychosis
1 Department of Psychiatry and Health Behavior, Georgia Regents University, Augusta, GA; 2Medical College of Georgia, Georgia Regents University, Augusta, GA
*To whom correspondence should be addressed; Department of Psychiatry and Health Behavior, Georgia Regents University, 997 Saint Sebastian Way, Augusta, GA 30912, US; tel: +1-706-721-4445, fax: +1-706-721-6602, e-mail: [email protected]
Introduction: A number of different infections are associated with acute psychosis. However, relationships between infections and acute psychosis in patients with schizophrenia have not been extensively explored. Exposure to Toxoplasma gondii is a replicated risk factor for schizophrenia. Previous studies have focused on T. gondii IgG antibodies, which are a marker of lifetime exposure, whereas IgM antibodies are a marker of acute/recent exposure, persistent infection, or reinfection. We performed a meta-analysis of T. gondii IgM antibodies and acute psychosis, to further investigate whether infections may be associated with relapse in schizophrenia. Methods: We identified articles by systematic searches of PubMed, PsycINFO, and ISI databases. We included studies, in English, of serum T. gondii IgM antibodies in patients with acute psychosis and controls. Results: Sixteen independent samples (2353 patients and 1707 controls) met inclusion criteria. Data were pooled using a random effects model. There was a significant increase in risk of positive T. gondii IgM antibodies in acute psychosis compared with controls (7.6% vs 5.7%, OR = 1.68, 95% CI = 1.23–2.27, P = .001). The association was stronger for patients with chronic schizophrenia (8.7% vs 4.6%, OR = 2.54, 95% CI = 1.63–3.96, P < .001) than first-episode psychosis. In meta-regression analyses, age, sex, and publication year were unrelated to the association; however, there was a significant association with geographic region. Discussion: An increased seroprevalence of T. gondii IgM in patients with acute psychosis complements and extends previous findings, suggesting that infections may be relevant to the etiopathophysiology of relapse in some patients with schizophrenia. Key words: infection/toxoplasmosis/psychosis/relapse/ meta-analysis Introduction Schizophrenia is associated with increased infections across the lifespan. Prenatal maternal infection, with a
variety of different infectious agents, is a replicated risk factor for schizophrenia1 and may act synergistically with family history of psychosis.2 Hospital contact for infection during childhood or adolescence is associated with an increased risk of schizophrenia.3 Schizophrenia is also associated with increased mortality from infectious diseases, including pneumonia and influenza.4,5 Outside of schizophrenia, a number of different viral, bacterial, and parasitic infections are associated with acute psychosis, a notable example being geriatric patients with psychosis and a comorbid urinary tract infection (UTI) in the context of either dementia or delirium.6,7 However, relationships between infections and acute psychosis in patients with schizophrenia have not been extensively explored. Acute psychosis is common and relapse prevention represents an important treatment issue in schizophrenia. Robinson et al8 found that 82% of patients with firstepisode psychosis (FEP) had an illness relapse within 5 years after recovery, and a majority had multiple relapses. Illness relapse is associated with adverse outcomes, including increased treatment-resistant symptoms, cognitive decline, and functional disability.9–11 Thus, to better understand and predict relapse in schizophrenia is a compelling opportunity and public health priority. Exposure to Toxoplasma gondii is a robust risk factor for schizophrenia. A meta-analysis found that subjects with FEP have a 2.5-fold increased risk of lifetime infection compared with controls, and a similar 2.7-fold increased risk of lifetime infection across all clinical phases of schizophrenia.12 Most previous studies have focused on T. gondii IgG antibodies, which are a marker of lifetime exposure to toxoplasmosis, whereas IgM antibodies are a marker of acute/recent infection,13 or also potentially persistent infection or reinfection, possibly with a different genotype.14–18 The objective of this study was to perform a meta-analysis of the association between T. gondii IgM antibodies and acute psychosis in schizophrenia, to further investigate whether infections may be associated
© The Author 2014. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For permissions, please email: [email protected]
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Joel M. Monroe1, Peter F. Buckley2, and Brian J. Miller*,1
J. M. Monroe et al
with relapse in schizophrenia. We hypothesize that there is an increased seroprevalence of T. gondii antibodies in patients with acute psychosis compared with controls. Methods Study Selection
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Data Extraction and Meta-Analysis Data were extracted for sample size and number of subjects seropositive for T. gondii IgM antibodies for acute psychosis and controls in each study. We also extracted descriptive data on geographic location, assay method, age, and sex. One author (B.J.M.) extracted all data, which was independently verified by another author (J.M.M.). Effect size estimates (ORs and 95% CIs) were aggregated utilizing the random effects method of DerSimonian and Laird.47 Random effects methods are considered to be more representative of real-world data in comparison to the alternative fixed effect approach48 and provide a more conservative estimate of the average weighted effect size.49 Random effects models also yield their actual first error rate while fixed effect models tend to inflate their first error rate. CIs obtained by fixed effect models are also biased and their actual coverage rate is smaller than their nominal coverage rate.50 Three studies that otherwise met the inclusion criteria could not be analyzed in the random effects meta-analysis because the prevalence of T. gondii IgM antibodies was zero for both acute psychosis and control groups, which results in an OR and 95% CI that is undefined.23,29,32 The main statistical hypothesis was that the ORs for the seroprevalence of T. gondii IgM in patients with acute psychosis vs controls equals 1.00. In a secondary analysis, we repeated the meta-analysis procedure for studies of FEP and chronic schizophrenia (each vs controls) considered separately. The meta-analysis procedure also calculates a χ2 value for the heterogeneity in effect size estimates, which is based on Cochran’s Q-statistic,51 and I2, the proportion of the variation in effect size attributable to between-study heterogeneity. Between-study heterogeneity χ2 was considered significant for P < .10.52 For all studies, and studies of chronic schizophrenia, between-study heterogeneity χ2 was significant, so we performed a sensitivity analysis. This was done by removing one study at a time and repeating the meta-analysis procedure, to examine its impact on the OR and between-study heterogeneity.53 Given
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Studies of T. gondii IgM antibodies in schizophrenia were systematically searched using Medline (PubMed, National Center for Biotechnology Information, US National Library of Medicine, Bethesda, MD), PsycINFO (via Ovid, American Psychological Association, Washington, DC), and Thomson Reuters (formerly ISI) Web of Knowledge (Science Citation Index and Social Sciences Citation Index, Thomson Reuters, Charlottesville, VA) from 1953 (when the first known study of T. gondii antibodies in patients with psychosis was published) through October 26, 2013, when the final search procedure was conducted. The primary search strategy was “(toxoplasma OR toxoplasmosis) AND (psychosis OR schizophrenia),” which yielded 160 articles from PubMed, 78 for PsycINFO, and 251 for ISI. Titles and abstracts of the resulting matches were screened for relevance to the present meta-analysis. The inclusion criteria were (1) case-control studies of serum T. gondii IgM antibodies in patients with acute psychosis in the context of schizophrenia or related psychotic spectrum disorders (including schizophreniform disorder, brief psychotic disorder, psychotic disorder not otherwise specified, delusional disorder, and schizoaffective disorder) and healthy controls, (2) the study had to be published, and (3) studies or abstracts had to be written in English. Patients with acute psychosis were further stratified by FEP or chronic schizophrenia. For studies that included patients with both FEP and chronic schizophrenia, if stratified data were not presented in the manuscript, we attempted to contact study authors. The exclusion criteria were: (1) studies that measured T. gondii IgG, but not IgM antibodies, (2) studies without a control group, (3) significant overlap in study population, (4) studies that assayed prenatal or antenatal samples, (5) studies of subjects at clinical high risk for psychosis, (6) studies of subjects with affective psychosis, and (7) review articles without primary data. For studies that measured both anti-T. gondii IgG and IgM antibodies, if stratified data were not presented in the manuscript, we attempted to contact study authors. From these sources, as well as a hand-searched review of reference lists, we identified 116 studies for potential inclusion. We did not employ formal search software and all publications were retrieved and examined in full text. Based on a preliminary review of these matches, 28 studies presented data on T. gondii IgM antibodies and warranted further consideration.19–46 These studies are summarized in table 1. The majority of initial matches were excluded because they did not present data on
T. gondii IgM antibodies or were review articles. After independent searches, detailed review of study methods by 2 authors (J.M.M. and B.J.M.) and attempts to contact study authors, 16 studies met the inclusion criteria, with 4 studies of FEP, 10 studies of chronic schizophrenia, and 2 studies of both FEP and chronic schizophrenia (15–30). Twelve studies were excluded from the final analysis due to: data on the prevalence of positive IgM antibodies not available (n = 5), uncertainty if patients were experiencing acute psychosis (n = 3), no control group (n = 2), patients not experiencing acute psychosis (n = 1), and significant overlap in study population (n = 1). There was universal agreement on the included studies. A flowchart summarizing the study selection process is presented in figure 1.
Meta-Analysis of Toxo IgM in Acute Psychosis
Table 1. Studies of Anti-Toxoplasma gondii IgM Antibodies in Schizophrenia IgM+ (n, %) Location
Status
Psychosis Control
Alvarado-Esquivel et al19 Alvarado-Esquivel et al20 Cetinkaya et al21 Daryani et al22 Dogruman-Al et al23 Hamidinejat et al24 Krause et al25 Liu et al26 Mahmoud and Hasan27 Tamer et al28 Yuksel et al29 Saraei-Sahnesaraei et al30 Hamidinejat et al24 James et al31
Mexico Mexico Turkey Iran Turkey Iran Germany China Iraq Turkey Turkey Iran Iran Nigeria
Chronic Chronic Chronic Chronic Chronic Chronic Chronic Chronic Chronic Chronic Chronic Chronic/FEP FEP FEP
3 7.9 2 4.0 1 1.0 30 37.5 0 0.0 2 3.4 1 3.2 49 10.3 2 2.1 2 5.0 0 0.0 15 14.4 2 5.0 10 7.1
Tanyuksel et al32 Wang et al33 Yolken et al34
Turkey China Germany
FEP FEP FEP
0 0.0 32 5.3 5 13.2
Total—included Bachmann et al35 Dickerson et al36
Not specified United States
156 FEP 34 Chronic/FEP 302
Dickerson et al37
United States
Chronic/FEP
Hinze-Selch et al38
Germany
Chronic
Hinze-Selch et al39
Germany
6.6
Mean Age Comment/Assay (Years) Male (%) Included Method
4 2.2 42.7 0 0.0 45.1 0 0.0 37.2 36 36.4 33.4 0 0.0 33.9 2 4.2 33.0 0 0.0 35.2 0 0.0 29.3 0 0.0 38.3 1 2.7 33.0 0 0.0 42.6 23 20.2 2 4.2 12 8.6 28.7 0 5 1 86
0.0 25.8 2.5 22.6 3.7 27.0 5.0
70.3 80.0 49.3 56.3 59.0 51.8 53.1 39.6 60.0
Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes
91.2 47.0
Yes Yes Yes
207
25.5 35.4
47.1 51.3
No No
314
34.6
51.8
No
344
214
38.3
43.6
No
Chronic
277
214
37.4
Holub et al40 Juanah et al41
Czech Republic Chronic Malaysia Unclear
0 1
Leweke et al42
Not specified
Multiple
Ling et al43
China
FEP
Nascimento et al44
Brazil
Outpatients
Niebuhr et al45
United States
Yonghua et al46
China
0.0 1.1
0 1
75
73
600
400
41
95
Unclear
180
532
Unclear
107
6.2
82
No
0.0 1.1
No No 29.8
77.3
No No
36.5
5.3
55.1
No
83.7
No No
ELISA ELISA ELISA ELISA ELISA ELISA ELISA ELISA ELISA ELISA ELISA ELISA ELISA Chromatographic immunoassay ELISA ELISA Immunoblot analysis No control group Data on IgM+ not available Data on IgM+ not available Data on IgM+ not available Study population overlap No control group Clinical status unclear Data on IgM+ not available Data on IgM+ not available No acute psychosis Clinical status unclear Clinical status unclear
Note: ELISA, enzyme-linked immunosorbent assay; FEP, first-episode psychosis.
the significant heterogeneity in the overall result, we also performed a series of meta-regressions to explore possible moderating variables to account for such heterogeneity. Meta-regression assesses and adjusts the effects of potential moderating variables on the effect size estimate from the meta-analysis (much in the same way that regression assesses the relationships between moderating variables and a dependent variable). A positive slope (ie, regression coefficient) means that the effect size estimate from the meta-analysis and the moderator variable change in the same direction, and a negative slope means they change in the opposite
direction. We conducted meta-regression analyses of age, sex, geographic location (latitude and longitude, considered separately, as well as region), and year of publication. As 14 of the 16 studies measured T. gondii IgM using enzyme-linked immunosorbent assay, we did not perform a meta-regression with assay method. Potential for publication bias was examined by means of Sterne’s funnel plot analysis54 and Egger’s regression intercept.55 The statistical analyses were performed in Stata 10.0 (StataCorp LP).56 All tests were 2-sided, and P values were considered statistically significant at the α = .05 level. Page 3 of 10
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Study
J. M. Monroe et al
Search Strategy: "(toxoplasma OR toxoplasmosis) AND (psychosis OR schizophrenia)” 3 databases searched: Medline PsycInfo Thomson Reuters Web of Knowledge Plus manual review of reference lists.
(n=160) (n=78) (n=251)
N=90 excluded, most commonly due to:
1) Measured anti-Toxoplasma gondii IgG, but not IgM 2) Review articles
N=28 Studies with data on anti-Toxoplasma gondii IgM Antibodies warranting further review
N=12 excluded: n=5 n=3 n=2 n=1 n=1
Data on the prevalence of IgM+ not available Unclear if patients experiencing acute psychosis No control group Patients not experiencing acute psychosis Significant study population overlap
N=16 Studies included in the meta-analysis n=4 n=10 n=2
First-episode psychosis (FEP) Chronic schizophrenia FEP and chronic schizophrenia
Fig. 1. Flowchart of the study selection process.
Results As described in table 1, search procedures yielded 16 independent studies, comprising 2353 patients with acute psychosis (including 818 subjects with FEP) and 1707 controls for inclusion in the meta-analysis. In all studies, there was a significant increase in risk of seropositive T. gondii IgM antibodies in acute psychosis compared with controls (7.6% vs 5.7%, OR = 1.68, 95% CI = 1.23– 2.27, P = .001). There was significant heterogeneity in this estimate (χ2 = 22.05, P = .055; I2 = 41.1%). In a sensitivity analysis, the heterogeneity remained significant after removal of each individual study. However, after removing the 2 studies with the highest seroprevalence of positive IgM antibodies in controls,22,30 the association was notably stronger (6.1% vs 2.4%, OR = 2.81, 95% CI = 1.80–4.37, P < .001) and the heterogeneity was no longer statistically significant (χ2 = 15.82, P = .148; I2 = 30.5%). In studies of acute psychosis in the context of chronic schizophrenia, the association with T. gondii IgM antibodies was stronger (8.7% vs 4.6%, OR = 2.54, 95% CI = 1.63–3.96, P < .001), but there was significant Page 4 of 10
heterogeneity in this estimate (χ2 = 15.52, P = .050; I2 = 48.5%). In a sensitivity analysis, the association was notably stronger (6.5% vs 0.9%, OR = 6.89, 95% CI = 3.10– 15.34, P < .001) and the heterogeneity was no longer statistically significant (χ2 = 9.30, P = .232; I2 = 24.8%) after excluding one study.22 In studies of FEP, there was a nonsignificant increase in T. gondii IgM antibodies compared with controls (5.7% vs 4.6%, OR = 1.47, 95% CI = 0.84–2.58, P = .181) and the heterogeneity was not significant (χ2 = 3.19, P = .363; I2 = 5.9%). Forest plots for the meta-analyses are presented as figure 2. A funnel plot display for data derived from all studies included in the meta-analysis (figure 2) and results of Egger’s test (intercept = 1.04, 95% CI = −0.33 to 2.41, P = .118) showed no evidence for potential publication bias. In meta-regression analyses, age, sex, latitude and longitude, and year of publication were all unrelated to the association between T. gondii IgM antibodies and acute psychosis (P > .05 for each), meaning they were not associated with T. gondii IgM seropositivity. However, there was a significant association with geographic region
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N=118 Potential studies for meta-analysis
Meta-Analysis of Toxo IgM in Acute Psychosis
2a. All studies
2b. Chronic Schizophrenia
%
Study ID
OR (95% CI)
W eight
Alvarado-Esquivel 2006
3.77 (0.81, 17.60)
1.92
Alvarado-Esquivel 2011
15.52 (0.73, 328.78)
0.36
Cetinkaya 2007
1.52 (0.06, 38.05)
0.98
Daryani 2010
1.05 (0.57, 1.93)
30.13
Hamidinejat 2010
0.82 (0.11, 6.06)
Krause 2010
%
Study ID
OR (95% CI)
Weight
3.77 (0.81, 17.60)
4.76
15.52 (0.73, 328.78)
0.89
3.17
Cetinkaya 2007
1.52 (0.06, 38.05)
2.43
3.00 (0.12, 76.58)
0.73
Daryani 2010
1.05 (0.57, 1.93)
74.53
Liu 2011
48.63 (2.99, 792.32)
0.93
Hamidinejat 2010
0.82 (0.11, 6.06)
7.83
Krause 2010
3.00 (0.12, 76.58)
1.79
Liu 2011
48.63 (2.99, 792.32)
2.30
Mahmoud 2009
5.11 (0.24, 107.77)
1.81
Tamer 2008
1.89 (0.16, 21.81)
3.66
Dogruman-Al 2009
(Excluded)
0.00
Yuksel 2010
(Excluded)
0.00
Overall (I-squared = 48.5%, p = 0.050)
2.54 (1.63, 3.96)
100.00
Mahmoud 2009
5.11 (0.24, 107.77)
0.73
Tamer 2008
1.89 (0.16, 21.81)
1.48
Saraei-Sahnesaraei 2009
0.67 (0.33, 1.36)
28.13
Hamidinejat 2010
1.21 (0.16, 9.00)
2.59
James 2013
0.82 (0.34, 1.97)
16.69
W ang 2006
2.20 (0.84, 5.72)
10.64
Yolken 2001
3.94 (0.43, 35.83)
1.52
Dogruman-Al 2009
(Excluded)
0.00
Yuksel 2010
(Excluded)
0.00
Tanyuksel 2010
(Excluded)
0.00
Overall (I-squared = 41.1%, p = 0.055)
1.68 (1.23, 2.27)
100.00
.1
1
.1
10
2c. First-Episode Psychosis
1
10
2d. Funnel Plot for All Studies
Anti-Toxoplasma gondii IgM Ab Funnel plot with pseudo 95% confidence limits
%
0
Study
OR (95% CI)
Weight
Hamidinejat 2010
1.21 (0.16, 9.00)
8.23
James 2013
0.82 (0.34, 1.97)
53.10
Wang 2006
2.20 (0.84, 5.72)
33.83
Yolken 2001
3.94 (0.43, 35.83)
4.84
Tanyuksel 2010
(Excluded)
0.00
Overall (I-squared = 5.9%, p = 0.363)
1.47 (0.84, 2.58)
100.00
1.5
1
.5
ID
.1
1
10
logor
5
10
15
Fig. 2. Meta-analysis of Anti-Toxoplasma gondii IgM antibodies.
(slope = −0.41, 95% CI = −0.80 to −0.01, P = .044), with a stronger association in studies from Asia, Europe, and South America (regions with a lower prevalence of T. gondii IgM positive controls), than in studies from Africa and the Middle East (figure 3). Discussion The present study consisted of a meta-analytic review of the association between T. gondii IgM antibodies and acute psychosis in patients with schizophrenia and healthy controls. We found a significant, 1.7-fold increased risk of T. gondii IgM antibodies in subjects with acute psychosis, of whom 7.6% were seropositive. This association was not moderated by age, sex, or year of publication. However, the association was moderated by geographic
region, with greater effect sizes in studies from Asia, Europe, and South America. An important strength of our study is that we considered T. gondii IgM antibodies, whereas previous studies have focused primarily on T. gondii IgG antibodies, which are a marker of lifetime exposure to toxoplasmosis.12 T. gondii IgM antibodies could represent either an acute/ recent infection,13 or also potentially persistent infection or reinfection, possibly with a different genotype.14–18 Thus, our work complements and extends previous findings, raising the possibility that exposure to T. gondii is not only an important risk factor for schizophrenia, but may also be associated with relapse in schizophrenia. Another strength of the present study is that we performed meta-regression analyses to consider moderating effects of age, sex, geography, and publication year. Page 5 of 10
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Alvarado-Esquivel 2006 Alvarado-Esquivel 2011
-.5 1
Geographic Region 1 2 3 4 5
South America Asia Europe Middle East Africa
2
3 geography
Studies (n) 2 2 2 9 1
4
5
% IgM+ Schizophrenia Control 5.7 1.2 7.5 1.2 8.7 1.8 5.5 8.3 7.1 8.6
Fig. 3. Meta-regression analysis of the effects of geographic region on the association between anti-Toxoplasma gondii IgM and acute psychosis.
Previous studies have found a prevalence of T. gondii IgM antibodies of 0.3% in healthy blood donors from Taiwan,57 1.6% in Italian women of childbearing age,58 2.1% in a general population sample in Mexico,59 2.4% among blood donors from the Czech Republic,60 and 4.6% among healthy volunteers in Nigeria,61 all of which are lower than the 5.7% prevalence in controls included in this meta-analysis, which raises the possibility of selection bias. However, the higher prevalence of T. gondii IgM antibodies in our controls would bias the OR toward the null hypothesis of no association with acute psychosis. Furthermore, the 2 studies removed in the sensitivity analysis also had the highest prevalence of subjects (both patients and controls) with T. gondii IgM antibodies. When these 2 studies were removed, the prevalence of T. gondii IgM antibodies in controls decreased to 2.4%, which is comparable with other general population studies cited above. Thus, although this approach could increase the OR by decreasing the prevalence of T. gondii IgM antibodies in controls, the statistical significance in both analyses points to an association that is not the result of bias. In a post-hoc analysis, we considered the effect of dropping the 3 studies where no subjects had positive T. gondii IgM antibodies. We calculated the prevalence of positive T. gondii IgM antibodies, using absolute numbers rather than calculating ORs and 95% CIs for individual studies, with these 3 studies included. We then calculated an overall OR and 95% CI for the prevalence of positive T. gondii IgM in patients with acute psychosis vs controls. In all studies, the significant increase in risk of seropositive Page 6 of 10
T. gondii IgM antibodies in acute psychosis compared with controls remained (6.6% vs 5.0%, OR = 1.34, 95% CI = 1.02–1.75, P = .035). Furthermore, in studies of acute psychosis in the context of chronic schizophrenia, the significant association with T. gondii IgM antibodies also remained (6.8% vs 3.8%, OR = 1.85, 95% CI = 1.28–2.68, P = .001). We also note that all 3 studies with no positive T. gondii IgM subjects were from Turkey. Two other included studies from Turkey had a very low prevalence of positive T. gondii IgM in patients (2.1%, 3 of 140) and controls (1.1%, 1 of 87), suggesting a regionspecific effect. These findings support the robustness of the overall association. We also performed subgroup analyses, comparing chronic schizophrenia and FEP separately. We found a significant association between acute psychosis and acute/recent toxoplasmosis in chronic schizophrenia, but a nonsignificantly increased risk in FEP. One possible explanation for this finding is that our study lacked sufficient statistical power to detect an association in FEP, as the sample size for FEP was approximately half that for chronic schizophrenia. Post-hoc calculations revealed that a total sample of 4078 subjects (2039 patients and controls) would be required to have 80% power to detect a minimum OR of 1.47, assuming a 4.6% prevalence of positive T. gondii IgM in controls. Alternatively, it is possible that the association with T. gondii IgM exists for relapse of chronic schizophrenia, but not FEP. Although the association was not moderated by age, it is possible that subjects with a longer duration of psychotic illness could have greater exposure to infectious agents than subjects with FEP due to illness-related factors. There are several limitations of the present study. Only a subset of published studies on T. gondii and schizophrenia met the inclusion criteria. Many excluded studies measured T. gondii IgG, but not IgM antibodies. Included studies may have used different assay methodologies and “cut-off points” for determining IgM positivity, but corresponding data were not presented. Data on the IgG status of patients seropositive for IgM antibodies were generally not available, which could inform on whether IgM positivity represents acute/recent infection, persistent infection, or reactivation of a latent infection. Data were also not available to confirm whether subjects with positive T. gondii IgM antibodies had clinical signs and/or symptoms of acute infection. Several other studies that measured IgM antibodies were excluded because data were not reported as the prevalence of IgM-positive subjects. Although our findings are subject to a potential selection bias, we attempted to mitigate this effect by contacting study authors to either clarify information or to request summary data to facilitate comparison with other studies. Another limitation is that we were not able to control for other potential confounding factors such as the uniformity of diagnoses across studies, definitions of relapse and first episode, duration of illness, number of
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0
logor .5
1
1.5
J. M. Monroe et al
Meta-Analysis of Toxo IgM in Acute Psychosis
infection (including cytomegalovirus, herpes simplex virus type 1, mumps, measles, and Japanese encephalitis virus) in parallel with their clinical syndrome, based on diagnostic (ie, 4-fold) changes in paired antibody titers. Fellerhoff et al68 found a 9.4-fold increased risk of chlamydial infection in 72 patients hospitalized for schizophrenia compared with 225 controls (40.3% vs 6.7%). Ahokas et al.69 found that 37% of 54 acutely ill psychiatric patients had evidence of viral infection in parallel with acute psychiatric symptoms, also based on diagnostic changes in paired antibody titers. Although diagnosis information was not available for this study, it is reasonable to assume many of these patients were experiencing acute psychosis. Krause et al25 found a 9.7% prevalence of cytomegalovirus IgM antibodies among 31 inpatients with schizophrenia, vs 0% in 30 healthy controls. Given associations between different infectious exposures, these findings suggest that a rigorously designed longitudinal study is warranted to investigate issues of causality and temporality regarding associations with acute psychosis. The association between T. gondii IgM and acute psychosis also warrants replication in other samples from diverse geographic regions. Most importantly, in order to further understand and clarify the biological relevance of this association, longitudinal studies are needed, with serial measurement of both anti-T. gondii IgM and IgG antibody titers in relation to the clinical course of schizophrenia. Future studies should investigate this association in stable outpatients with schizophrenia, to evaluate whether it is more specific to episodes of illness relapse or schizophrenia in general. Replicated findings in well-controlled studies would suggest adjunctive treatment with antitoxoplasmosis agents might be a novel therapeutic strategy in antibody-positive patients. Given that several different acute infections may be increased in patients with acute psychosis in the context of schizophrenia, this association could also be explored with other common infections, such as cellulitis and pneumonia. Taken together, acute/recent infections appear increasingly relevant to the psychotic relapse in some patients with schizophrenia. Funding In the past 3 years, Dr B.J.M. has received grant support from the National Institute of Mental Health (K23MH098014) and Georgia Regents University, and research support from the National Institutes of Health Clinical Loan Repayment Program. Acknowledgments The authors wish to thank Drs Faith Dickerson, Cosme Alvarado-Esquivel, Bawo James, Bekir Kocazeybek, and Zhao-Rong Lun for sharing data and/or articles. The Page 7 of 10
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lifetime episodes of acute psychosis (and whether or not prior episodes were associated with T. gondii), the duration of clinical stability prior to acute psychosis, exposure to cats, consumption of raw or undercooked meats, and antipsychotic medications. The impact of these factors on the association remains unclear. Although the association was moderated by geographic region, 9 of the 16 studies (56%) were performed in the Middle East, with no more than 2 studies in any other geographic region, including no studies in North America. Both geography62 and latitude63 may be associated with seroprevalence of T. gondii. Latitudinal variability may be due to local rainy conditions (oocysts live longer in more humid conditions) and low altitude regions. Factors contributing to geographic variability may include exposure to cats and/ or consumption of raw or undercooked meat. There is also evidence for different T. gondii serotypes based on geography, including serotype II in Europe and of serotypes I and III in South America.64 It is not clear whether this association is specific to acute psychosis or to schizophrenia in general. We identified only one study that measured T. gondii IgM antibodies in stable patients with schizophrenia,44 but the prevalence of positive antibodies was zero in both patient and control groups. While this finding could support an association that is specific to acute psychosis, it may also be due to a relatively small sample size, selection factors, or geographic factors. In addition, data on the seroprevalence of other comorbid infections, and factors that may have provoked the onset of acute psychosis, would permit a more comprehensive assessment of the potential for confounding and of other infections on these relapses. Our study also does not permit inferences regarding either temporal or causal aspects of this association. IgM antibodies can remain positive for months to 2 years after acute toxoplasmosis, and can also reemerge following reactivation of latent infection; thus, the timing of exposure relative to the episode of acute psychosis is unclear. One possibility is that acute psychosis, and the concurrent stress, could either increase vulnerability to exposure to toxoplasmosis (eg, a patient with disorganized behavior might be more likely to consume raw or undercooked meat), or cause a reactivation of latent infection. By contrast, it is possible that T. gondii infection precedes acute psychosis. A previous meta-analysis found an increased risk of T. gondii IgG antibodies in schizophrenia, suggesting that exposure often precedes illness onset.12 Several other studies have reported associations between acute/recent infections and acute psychosis. We have replicated an association between UTI and acute psychosis in patients with schizophrenia.65,66 In one of these studies, there was a significant association with UTI among acutely ill inpatients, but not stable outpatients with schizophrenia compared with controls.65 Srikanth et al67 found that 29% of 35 patients with acute psychosis had a definite, ongoing viral
J. M. Monroe et al
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authors also wish to thank Niju Philip for assistance with manuscript preparation and Billy Houke for assistance with references. Contributors: Dr B.J.M. designed the study. Drs B.J.M. and J.M.M. managed the literature searches and the analyses. Drs P.F.B., B.J.M., and J.M.M. wrote the first draft of the manuscript. All authors contributed to and have approved the final manuscript. Dr J.M.M. has nothing to disclose. Dr P.F.B. is a consultant (Honorarium/Expenses) for the National Institute of Mental Health. B.J.M. has nothing to disclose for this work. In the past three years, Dr B.J.M. has received consultancy fees for surveys from Medefied Europe and MDLinx.com, and speaker fees for grand rounds lectures from Emory University and the Zucker-Hillside Hospital.
Meta-Analysis of Toxo IgM in Acute Psychosis
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