Schizophrenia Bulletin vol. 33 no. 3 pp.

782788, 2007
doi:10.1093/schbul/sbm010
Advance Access publication on March 26, 2007

A Controlled Prospective Study of Toxoplasma gondii Infection in Individuals

With Schizophrenia: Beyond Seroprevalence

Dunja Hinze-Selch1,2, Walter Daubener3, Lena Eggert2,

Sukran Erdag2, Renate Stoltenberg3, and Sibylle Wilms2

Key words: infection/immunity/tryptophan/Toxoplasma

gondii, psychosis/depression

The Center for Integrative Psychiatry, Department of Psychiatry

and Psychotherapy, Christian-Albrechts-University, Niemannsweg 147, D-24105 Kiel, Germany; 3Institute for Medical Microbiology and Hospital Hygiene, Heinrich-Heine University,
Dusseldorf

Introduction
Chronic infection with the intracellular parasite Toxoplasma gondii (TG) is more frequent in individuals
with schizophrenia than in psychiatrically healthy controls, as indicated in several studies from different countries.1,2 Furthermore, first-episode patients might differ
from patients with recurrent or chronic course by having
more frequent TG infection and/or a more intense immune response.1,2 However, to date, the results are not
equivocal,1,2 with subjects generally characterized as
psychiatric patients being shown to be more frequently affected than healthy controls or nonpsychiatric
patients.36 A study on well-characterized psychiatric
patients with distinct diagnoses other than schizophrenia
has not yet been published. Moreover, studies with relevant additional data, such as the interrelationship with
psychiatric symptomatology and course of the disorder,
are still lacking.
Briefly, TG infection in humans takes place when infectious microcysts, typically in affected undercooked
and raw meat, are ingested or through contamination
with infected cat faeces.7 Because the infection is ubiquitous, the probability of becoming infected increases with
age, apart from any particular high-risk behavior, as
described before.
When TG infects an organism, it invades various cells8
and persists intracellularly, including in neurons and
glia.911 The host organism is not able to eradicate the
infection.7 However, immunocompetent hosts control
the chronic infection with a T-lymphocytedriven defense.12 All immunologic mechanisms involved have
not yet been unraveled, but it is known that interferon-gamma (IFN-c) and the enzyme indoleamine
2,3-dioxygenase (IDO) play a role.1317 Activated Thelper cells secrete IFN-c, which induces IDO. This enzyme degrades the tryptophan that is needed for the
tachyzoitic phase of TG. Consequently, activated parasites die by tryptophan depletion.13 The tryptophan degradation products that accumulate via the kynurenine

Toxoplasma gondii (TG) infection has been reported to be

more frequent in schizophrenia. The interaction of the lifelong persisting parasite with the hosts immune system
involves T-cell/interferon-gammainduced degradation of
tryptophan and provides a challenge to the host well beyond
a possible role in the etiology of schizophrenia. The hypothesis we tested in this study was that TG infection may be
more frequent (serofrequency) and/or more intense (serointensity) in patients with schizophrenia or major depression
compared with psychiatrically healthy controls. In addition, these measures are associated with the clinical course.
We did a cross-sectional, prospective investigation of individuals with schizophrenia (n = 277) and major depression
(n = 465) admitted to our department (20022005) and of
healthy controls (n = 214), with all groups adjusted for age
and geographic home region. Serofrequency was comparable between the groups, but serointensity was significantly
higher in the patients. In individuals with schizophrenia,
serointensity was significantly positively associated with
C-reactive protein levels and leukocyte counts, and firstepisode patients yielded significantly higher serotiters. Immunomodulatory medication was associated with decreased
serotiters. In addition, the route of infection appears to differ between patients and controls. Thus, our results support
increased host responses to TG infection in the patients, as
well as increased titers in first-episode patients with schizophrenia; this may relate to the shifted T-helper 1/2 status
described in these patients. Therefore, we suggest that TG
infection, particularly in individuals with schizophrenia,
is an important environmental factor in the interaction between psychiatric vulnerability, genetic background, immunomodulation, and the neurotransmitter systems.
1

To whom correspondence should be addressed; tel: 49-4319900-2554, fax: 49-431-9900-2568, e-mail: d.hinze-selch@
zip-kiel.de.

The Author 2007. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved.
For permissions, please email: journals.permissions@oxfordjournals.org.

782

Toxoplasma in Schizophrenia Beyond Seroprevalence

pathway18 may result in excess dopaminergic tone. Thus,

the host defense system might produce a lack of serotonin
and an accumulation of dopaminergic activity. Psychiatrically, this suggests depressive and psychotic syndromes.1922 Therefore, this parasitic chronic infection,
which shifts between silent and microactivated states23
in conjunction with the host defense system, presents
an attractive theoretical schema for increased serofrequencies of this infection in psychiatric patients with
affective and psychotic syndromes.
We hypothesized that TG infection might be more frequent and/or more intense in patients with schizophrenia
and in patients with major depression compared with
age-adjusted psychiatrically healthy controls. We rated
severity of the symptoms and the course of the disorder.
In addition, we analyzed general inflammatory measures,
took a careful medication history, and queried the subjects specifically about behaviors associated with a greater
risk of TG infection.
Methods
All patients who were admitted to inpatient units of our
department between 2002 and 2005 and who were diagnosed clinically with schizophrenia or major depression
were analyzed for their serotiters to TG infection from
blood drawn routinely at admission (including analysis
of C-reactive protein [CRP] and leukocyte count). The
patients were also rated by experienced psychiatrists
(Wilms and Erdag) for the severity of their symptomatology using the German version of the Clinical Global Impression rating scale (CGI), item 1 (07)24; this was then
collapsed to an arbitrary rating scale with 1 for none or
mild (1 or 3 in CGI), 2 for moderate (4 in CGI), and 3 for
severe symptoms (5 and 6 in CGI) because items 0, 2, and
7 of CGI had not been marked. In addition, the patients
were asked to complete a short questionnaire on risky
eating habits (now or ever consuming raw or undercooked meat at least several times) and close and risky
cat contacts (now or ever cat ownership, cat in the
same household, playing closely with cats, cleaning cat
litters). When a patient was discharged, the same experienced psychiatrists analyzed the patients records of the
admission and all records, if any, of prior admissions. Diagnoses were assigned according to International classification of Diseases, 10th Revision (ICD-10)25 using ICD-10
checklists.26 The course of the disorder for schizophrenia
and depression was rated by an arbitrary rating scale,
with 0 for first episode, 1 for recurrent course, and 2
for chronic course. In addition, patients with schizophrenia were rated for first episode, second episode, recurrent
episodes, and chronic course. Patients with acute or
chronic infectious or inflammatory processes otherwise
specified and with any major medical problems involving
the immune system were excluded. Nonpsychiatrically affected controls were recruited from the same geographic

region as the patients who are admitted to our department, which provides regional sectorized psychiatric
care. The controls had blood drawn for TG serology,
and they completed the questionnaires on risk behavior.
They were screened for psychiatric disorders and major
medical problems as well as for present or recent history
of infection or inflammation. This study was approved by
the local Ethics Committee of the Faculty of Medicine at
the Christian-Albrechts-University, Kiel. All participants
gave informed consent to take part in the study.
Psychotropic medication use was categorized for statistical analysis as follows: regular vs on-demand use, antipsychotic medication by potency,27 typical vs atypical,
chemical structure, and all regular medication used by
any patients by immunomodulatory potency according
to human in vivo data (yes = amitriptylline,28 carbamazepine,29 clozapine,28 lithium,28,29 mirtazapine,30 and
olanzapine28; no = haloperidol,28 paroxetin,28 and venlafaxin30; and unknown/possible immunomodulation =
amisulpride, flupenthixol, levomepromazine, melperone,
perazine, perphenazine, pipamperone, promethazine,
quetiapine, risperidone, and ziprasidone, with respect
to antipsychotics).
TG serology was done by microbiologists (Daubener
and Stoltenberg) using the internationally established
and widely used Toxo-Spot IF (bioMerieux, Lyon,
France) according to the instruction of the supplier. Conventionally, for the detection of acute TG infections, the
titers are defined as follows: <1:16 negative, no infection;
1:161:256 positive immune reaction suggestive of
chronic infection; >1:256 positive, immune reaction suggestive of recent infection. However, we were interested in
differentiating low and high titers in our subjects on the
basis of microbiological and immunological expertise.
Thus, we collated the individual serotiters as follows:
<1:16 no contact with TG; 1:161:64 TG contact, lowtiter response; and
1:128 TG contact, intense individual
antibody reaction, high-titer response.
For statistical analysis, we used cross-tables and correlational analyses (SPSS for Windows 8.0). In order to test
whether certain additional variables had an impact on
our results, we tested these variables by cross-tables
and correlational analyses with our variables of interest.
If there were no significant results, we assumed that the
additional variables did not have a significant effect on
our results. The level of significance (2 tailed) was set
at P  .05. No adjustment of the error probabilities
for multiple testing was performed, because of the explorative nature of the study.
Results
Characteristics of the Patients and Controls
We included the following subjects in our study: 277
patients with schizophrenia (mean age 37.4 6 12.0 years
[range 18.792.1], of which 24% [n = 67] were older than
783

D. Hinze-Selch et al.

Fig. 1. Percentage of Toxoplasma gondiiPositive Subjects

Among All Controls Depending on Age.

45 years); 465 with unipolar major depression (mean age

46.0 6 15.5 years [range 18.292.3], of which 48% [n = 221]
were older than 45 years); and 214 healthy controls (mean
age 38.9 6 13.3 years [range 18.472.7], of which 26% [n =
55] were older than 45 years). For statistical reasons, the
larger the numbers per group, the more difficult the
matching becomes for one variable between the groups.
Therefore, it was not possible to age match all the groups
in our study. However, in order to deal with microbiologically relevant age effects with respect to TG serology in
the between-group analyses, we created subsets in each
group (over 45 years of age, and 45 years of age and under) because 45 years of age was a turning point in TG
serofrequency in our control group (figure 1). In the following sections, all results are reported separately for
these 2 age groups.
Gender and smoking habits did not significantly interfere with the data analyses to follow.
Data Analysis
With respect to serofrequency, the only significant difference between the diagnostic groups and controls was in
the individuals older than 45 years of age for titers
128.
As depicted in table 1, the frequency of TG infection (ie,
titer <16 vs titer
16) did not differ significantly between
the diagnostic groups and controls, whereas there was
a significant group difference when the comparison
was done by titer categories. There are significantly
more individuals with serotiters
128 in both patient
groups compared with the controls. Thus, the intensity
of the antibody response, ie, serointensity, is higher in

the patients than in the controls. The questionnaires

on cat contact and eating habits show that patient groups
and controls reported similar frequency of these risk
behaviors (data not shown). However, when analyzing
interrelationships between serofrequency and the items
in the questionnaires, we found that serofrequency is significantly associated with the eating of raw meat in all
patient groups, whereas in the controls there was an effect
of close and risky cat contact (table 2).
Further analyses of the schizophrenia group revealed
a significant positive correlation between the titer categories and the number of leukocytes (rho = 0.130, P = .043 by
Spearman correlation analysis). Moreover, high titers were
significantly associated with high CRP values (table 3).
With respect to the clinical course, first-episode patients
were significantly more likely to have high antibody
titers. Among the highantibody titer patients, there
are significantly more with first episode or chronic
course vs recurrent course (table 4). These effects
were not seen in seronegative or lowantibody titer
patients. Whereas age did not interfere with these
results, the use of antipsychotic medication with immunomodulatory or putative immunomodulatory effects
did play a role. Using such medication was significantly
correlated with lower antibody titers (rho = 0.118, P =
.024 by Spearman correlation analysis). Other characteristics of the medication status did not have significant
effects in our analysis.
Further analysis of the major depression group showed
significant effects for medication only. As can be seen in
table 5, TG seronegative patients were more likely to
have had no antidepressants, whereas the medium
antibody titer patients were most likely to have been
medicated with antidepressants. In addition, medium
antibody titer patients were more likely to have had
tri/tetracyclic antidepressants (TCA), whereas seronegative individuals were evenly balanced in the use of TCAs
vs selective serotonin reuptake inhibitors (SSRIs). The
seropositive individuals had been administered TCAs
significantly more often than SSRIs; monaminoxidase
(MAO) inhibitors were not used. Immunomodulatory
medication was more frequent in the medium antibody
titer patients, as depicted in table 6. The use of antipsychotic and mood-stabilizing medication did not show any

Table 1. Serofrequency and Serointensity Between Diagnostic Groups and Controls (age > 45 y)

N
Major depression
Schizophrenia
Controls

221
67
55

Titer < 16
Percentage

Titer 16-64
Percentage

Titer
128
Percentage

Titer
16
Percentage

31
45
35

55
42
62

14
13
3

69
55
65

Note: Chi-square test on titer < 16 vs titer
16: P = .117. Chi-square test on titer categories between groups: P = 0.05; the statistically
significant effect arises for titer
128.

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Toxoplasma in Schizophrenia Beyond Seroprevalence

Table 2. Eating Habits in all Patients Groups and Risky Cat Contact in the Healthy Controls
Patients
N

Controls
Raw Meat 
Percentage

Raw Meat
Percentage

Cat Contact 
Percentage

Cat Contact
Percentage

Titer < 16
Titer 16-64
Titer
128

322
235
67

54
38
43

46
62
57

120
72
11

47
43
9

53
57
91

Titer
16

302

39

61

83

39

61

Note: Chi-square test on eating habits by serofrequency in both patients groups: P = .001 with significant interrelationships between
consumption of raw meat and seropositivity. Chi-square test on risky cat contact by serofrequency in all healthy controls: P = .05 with
significant interrelationships between risky cat contact and seropositivity.

significant interrelationship with the TG antibody titer

data.

Discussion
We have presented the first controlled, age-adjusted, prospective, large study of TG infection in psychiatric
patients with schizophrenia and major depression diagnosed according to ICD-10 and all recruited in the
same geographic region and during the same period.
We found that serofrequency (titer <1:16 vs titer

1:16) did not differ between groups but that serointensity (<1:16 vs 1:161:64 vs
1:128) did differ between
patients and controls, with higher serointensity in the
patients. The analyses of interrelationships within each
group between the TG antibody titers and further immunologic or psychopathologic parameters revealed significant results for the schizophrenia group only. High
antibody titers were associated with higher inflammatory
responses and with first-episode status.
The unique meta-analysis by Torrey and coworkers31
of all published studies included only well-described and
methodologically sound studies and calculated an odds
ratio of average 2.73. There was no systematic effect of
the size of the groups and the results. The number of studTable 3. CRP Values and Titer Categories in the Group
Schizophrenia

CRP < 6 [mg/l]

Percentage

CRP
6 [mg/l]
Percentage

Titer < 16
Titer 16-64
Titer
128

147
75
22

88
77
64

12
23
36

Titer
16

97

74

26

Note: Chi-square test on interrelationships between titer

categories and CRP values: P = .005, with significant
interrelationships between high CRP values and titer
128.

ies with control groups matched by any means to the patient groups is low, ie, 4 of 23, of which 3 dealt with firstepisode patients only. For these 4 studies, the odds ratios
range between 2.19 and 5.45. We cannot explain these
discrepancies between different studies. However, we
suggest for consideration the following issue: matching
of the comparison groups is important with respect to
age and geographic region of residence (particularly urban vs rural) for the likelihood of acquiring the infection.32 We matched for both of these criteria, whereas
none of the previously published studies did so. From
our experience, controlling for age is essential. Slight differences in mean age, particularly disequilibrium between
the microbiologically relevant age blocks, may shift the
results. If we had compared the groups without adjusting
for age, seropositives would have been significantly more
frequent in the oldest group of patients with major depression. Thus, we think that studies that do not carefully
adjust for age between groups must be considered with
caution. Furthermore, studies that report increased antibody levels in patients must be carefully evaluated because increased antibody levels are not identical to
increased frequency of seropositives.33,34
Our study is the first that also systematically collected
information on the putative routes of infection. Patients
and controls did not differ with respect to the frequency
of these risk factors, but they did differ with respect to the
interrelationship between these risk factors and seropositivity: the eating of raw meat in the patients and risky cat
contact in the controls were associated with higher seropositivity. Thus, if this association points to the infectious
route, our patients might have eaten infected raw meat
more often, and the controls might have been hygienically less careful in their contacts with infected cats.
On the basis of our data, we cannot further analyze
this issue. However, if there is particular risk behavior
in psychiatric patients, it would be useful to know this
and to specifically intervene.
We found that serotiters were significantly higher in
the 2 patient groups compared with the controls in all
785

D. Hinze-Selch et al.

Table 4. Serointensity and Clinical Course in the Group Schizophrenia

First episode
Second episode
Recurrent episodes
Chronic course

Titer < 16
Percentage

Titer 16-64
Percentage

Titer
128
Percentage

Titer
16
Percentage

37
73
27
105

59\15
62\30
67\12
61\43

39\10
36\36
26\10
31\44

23\40
3\10
7\10
8\40

41\16
38\30
33\10
39\44

Note: Chi-square test on the interrelationships between titer categories and clinical course: P = .037 with significant interrelationships
between titer
128 and first episode or chronic course as well as between first episode and titer
128; percent figure preceding \ refers
to the line and percent figure following \ refers to the column.

individuals older than 45 years. Moreover, the patients

with schizophrenia demonstrated significant interrelationships between the titer category (serointensity) and
the course of the disorder as well as with inflammatory
variables and the use of immunomodulatory medications. Our results are consistent with previous studies
that found increased serotiters in first-episode patients
with schizophrenia.33,34 As mentioned before, increased
serotiters are not necessarily in the range of the microbiologically high titers suggestive of recent infection and,
therefore, might rather support the more intense antibody response of the host.35 Consequently, the higher
antibody titers in the first-episode patients, regardless
of age, might be based on the special condition of
the patients. This is further supported by the additional
interrelationship between high antibody titers and
increased CRP levels and numbers of leukocytes as
markers of inflammatory activity. There is a vast literature on immunologic peculiarities in individuals with
schizophrenia.1,3640 In the light of TG infection, these
data are of special interest.1,36 As mentioned previously,
one basic host defense strategy is through proinflammatory T-helper lymphocytes, ie, TH1 cells.12,13 It was described that individuals with schizophrenia with acute

symptomatology display increased TH1-associated cytokine responses, returning to control levels during successful antipsychotic treatment.41 Therefore, an infection
such as TG might recurrently induce a TH1 response
that modulates the serotonin and dopamine neurotransmitter systems, leading to respective psychotic symptomatology. Antipsychotic treatment that reorganizes these
neurotransmitter systems reduces the symptoms by modulating this common final pathway. Immunomodulating
antipsychotics28,37,42 in addition might become involved
in the host defense against this infection. We found that
the use of immunomodulating antipsychotics was associated with lower TG titers. We suggest that the cytokine
pattern of increased TH1 response in patients with acute
symptoms might be caused by the proinflammatory response to infections such as TG. To our knowledge, there
is no published study that investigated TG infection and
TH1 immune variables simultaneously. Such a study will
be necessary to determine whether TG infections in individuals with schizophrenia are associated with increased
TH1 activation; it might also provide an explanation for
the diverse findings in schizophrenia on the overactivation of TH1 or TH2 cytokines (for review of the TH2
hypothesis of schizophrenia see Schwarz39).

Table 5. Use of Antidepressants and Titer Category in the Group

Major Depression

Table 6. Use of Immunomodulatory Medication and Titer

Category in the Group Major Depression

No AD
Percentage

SSRI
Percentage

TCA
Percentage

Titer < 16
Titer 16-64
Titer
128

221
192
50

61\53
46\35
60\12

22\51
21\43
12\6

17\33
33\55
28\12

Titer
16

242

49\47

19\49

32\67

Note: Chi-square test on the interrelationships between use of

antidepressants and titer categories: P = .002 with significant
interrelationships between seronegativity and no antidepressant
as well as between seropositivity and the use of TCAs; percent
figure preceding \ refers to the line and percent figure following \
refers to the column. No AD = no antidepressant medication,
SSRI = selective serotonin reuptake inhibitor as antidepressant
medication, TCA = tri-/tetracyclic antidepressant medication.

786

IM
Percentage

IM
Percentage

IM?
Percentage

Titer < 16
Titer 16-64
Titer
128

222
192
50

61\56
44\35
48\10

11\33
22\56
18\12

28\43
34\45
34\12

Titer
16

242

45\44

22\67

34\57

Note: Chi-square test on the interrelationships between the use

of immunomodulatory medication (IM = no, IM = yes,
IM? = questionable immunomodulation; for the individual
drugs, please, see Materials and Methods) and the titer
categories: P = .005 with significant interrelationships between
the use of immunomodulatory medication and titer 16-64;
percent figure preceding \ refers to the line and percent figure
following \ refers to the column.

Toxoplasma in Schizophrenia Beyond Seroprevalence

We found high TG titers in first-episode patients and

an association between high titers and increased CRP and
leukocyte values, as well as an association between the
use of immunomodulating antipsychotics and low titers.
One reason could be the use of immunomodulating antipsychotics from the first episode onward. On the other
hand, because the high titers were seen in both firstepisode and chronic-course patients, continuously high
titers might favor a chronic course. Furthermore, a strong
proinflammatory immune response to properly control
TG microcysts could be counterproductive. One can
speculate whether modulating this intense immune response might improve the clinical course in the patients
with high titers and chronic course, as well as prevent
the high-titer, first-episode patients from developing a
chronic course.
Even if our data cannot answer all the questions and
speculations presented, they represent the first detailed
data on several important variables, and they support
continued research on these questions. If TG infection
is really able to induce a proinflammatory immune response that leads to dysregulated serotonin and
dopamine neurotransmitter systems, to clinically relevant
psychiatric symptoms, and perhaps even to the precipitation of schizophrenia in vulnerable subjects,43 then a specific and effective treatment of this infection, coupled
with a better understanding of how this vulnerability is
defined, will be mandatory.

Acknowledgments
We thank The Stanley Medical Research Institute for the
generous support (grant # 01T-404). We appreciate the
excellent technical support of Susanne Kell, Imke
Petersen, Helga Dittmer, and Wilfried Schwippert. We
thank Elfriede Fritzer, for her statistical expertise, and
Dr Christine Miller for improving the use of English
language in our article. Last but not least, we thank all
our probands.

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