A Controlled Prospective Study of Toxoplasma gondii Infection in Individuals
With Schizophrenia: Beyond Seroprevalence
Dunja Hinze-Selch1,2, Walter Da ¨ubener3, Lena Eggert2,
Su ¨kran Erdag2, Renate Stoltenberg3, and Sibylle Wilms2
2The Center for Integrative Psychiatry, Department of Psychiatry
and Psychotherapy, Christian-Albrechts-University, Niemanns-
weg 147, D-24105 Kiel, Germany;3Institute for Medical Micro-
biology and Hospital Hygiene, Heinrich-Heine University,
Toxoplasma gondii (TG) infection has been reported to be
more frequent in schizophrenia. The interaction of the life-
long persisting parasite with the host’s immune system
involves T-cell/interferon-gamma–induced degradation of
tryptophanandprovides achallengetothehost wellbeyond
a possiblerole in the etiology of schizophrenia. The hypoth-
esis we tested in this study was that TG infection may be
more frequent (serofrequency) and/or more intense (seroin-
tensity) in patients with schizophrenia or major depression
compared with psychiatrically healthy controls. In addi-
tion, these measures are associated with the clinical course.
We did a cross-sectional, prospective investigation of indi-
viduals with schizophrenia (n = 277) and major depression
(n = 465) admitted to our department (2002–2005) and of
healthy controls (n = 214), with all groups adjusted for age
and geographic home region. Serofrequency was compara-
ble 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 first-
episode patients yielded significantly higher serotiters. Im-
serotiters. In addition, the route of infection appears to dif-
fer 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 schizo-
phrenia; 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 be-
nomodulation, and the neurotransmitter systems.
Key words: infection/immunity/tryptophan/Toxoplasma
Chronic infection with the intracellular parasite Toxo-
plasma gondii (TG) is more frequent in individuals
with schizophrenia than in psychiatrically healthy con-
trols, as indicated in several studies from different coun-
tries.1,2Furthermore, first-episode patients might differ
from patients with recurrent or chronic course by having
more frequent TG infection and/or a more intense im-
mune response.1,2However, to date, the results are not
equivocal,1,2with subjects generally characterized as
‘‘psychiatric patients’’ being shown to be more frequen-
tly affected than healthy controls or nonpsychiatric
patients.3–6A study on well-characterized psychiatric
patients with distinct diagnoses other than schizophrenia
has not yet been published. Moreover, studies with rele-
vant 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 in-
fectious microcysts, typically in affected undercooked
and raw meat, are ingested or through contamination
with infected cat faeces.7Because the infection is ubiqui-
tous, the probability of becoming infected increases with
age, apart from any particular high-risk behavior, as
When TG infects an organism, it invades various cells8
and persists intracellularly, including in neurons and
glia.9–11The host organism is not able to eradicate the
infection.7However, immunocompetent hosts control
the chronic infection with a T-lymphocyte–driven de-
fense.12All immunologic mechanisms involved have
not yet been unraveled, but it is known that inter-
feron-gamma (IFN-c) and the enzyme indoleamine
2,3-dioxygenase (IDO) play a role.13–17Activated T-
helper cells secrete IFN-c, which induces IDO. This en-
zyme degrades the tryptophan that is needed for the
tachyzoitic phase of TG. Consequently, activated para-
sites die by tryptophan depletion.13The tryptophan deg-
radation products that accumulate via the kynurenine
1To whom correspondence should be addressed; tel: þ49-431-
9900-2554, fax: þ49-431-9900-2568, e-mail: d.hinze-selch@
Schizophrenia Bulletin vol. 33 no. 3 pp. 782–788, 2007
Advance Access publication on March 26, 2007
? The Author 2007. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved.
For permissions, please email: email@example.com.
pathway18may result in excess dopaminergic tone. Thus,
and an accumulation of dopaminergic activity. Psychiat-
rically, this suggests depressive and psychotic syn-
dromes.19–22Therefore, 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 serofre-
quencies of this infection in psychiatric patients with
affective and psychotic syndromes.
We hypothesized that TG infection might be more fre-
quent 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 inflammatorymeasures,
took a careful medication history, and queried the sub-
risk of TG infection.
All patients who were admitted to inpatient units of our
department between 2002 and 2005 and who were diag-
nosed 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 symptomatol-
ogy using the German version of the Clinical Global Im-
pression rating scale (CGI), item 1 (0–7)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 under-
cooked 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 experi-
enced psychiatrists analyzed the patient’s records of the
admission and all records, if any, of prior admissions. Di-
agnoses were assigned according to International classifi-
checklists.26The 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 schizophre-
nia 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
fected controls were recruited from the same geographic
region as the patients who are admitted to our depart-
ment, 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
the local Ethics Committee of the Faculty of Medicine at
gave informed consent to take part in the study.
Psychotropic medication use was categorized for sta-
tistical analysis as follows: regular vs on-demand use, an-
tipsychotic medication by potency,27typical vs atypical,
chemical structure, and all regular medication used by
any patients by immunomodulatory potency according
to human in vivo data (yes = amitriptylline,28carbama-
olanzapine28; no = haloperidol,28paroxetin,28and venla-
faxin30; and unknown/possible immunomodulation =
amisulpride, flupenthixol, levomepromazine, melperone,
perazine, perphenazine, pipamperone, promethazine,
quetiapine, risperidone, and ziprasidone, with respect
TG serology was done by microbiologists (Da ¨ubener
and Stoltenberg) using the internationally established
and widely used Toxo-Spot IF (bioMerieux, Lyon,
France) according to the instruction of the supplier. Con-
ventionally, for the detection of acute TG infections, the
titers are defined as follows: <1:16 negative, no infection;
1:16–1:256 positive immune reaction suggestive of
chronic infection; >1:256 positive, immune reaction sug-
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; 1:16–1:64 TG contact, low-
titer response; and ?1:128 TG contact, intense individual
antibody reaction, high-titer response.
For statistical analysis, we used cross-tables and corre-
lational 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
ative nature of the study.
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 18.7–92.1], of which 24% [n = 67] were older than
Toxoplasma in Schizophrenia Beyond Seroprevalence
45 years); 465 with unipolar major depression (mean age
age 38.9 6 13.3 years [range 18.4–72.7], 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 todeal with microbiolog-
ically 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 un-
der) because 45 years of age was a turning point in TG
serofrequency in our control group (figure 1). In the fol-
lowing sections, all results are reported separately for
these 2 age groups.
Gender and smoking habits did not significantly inter-
fere with the data analyses to follow.
With respect to serofrequency, the only significant differ-
ence 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 sig-
nificantly associated with the eating of raw meat in all
of close and risky cat contact (table 2).
Further analyses of the schizophrenia group revealed
a significant positive correlation between the titer catego-
riesandthenumberofleukocytes(rho= 0.130,P= .043by
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 high–antibody 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 low–antibody titer
patients. Whereas age did not interfere with these
results, the use of antipsychotic medication with immu-
nomodulatory 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 character-
istics of the medication status did not have significant
effects in our analysis.
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 seronega-
tive 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 antipsy-
Fig. 1. Percentage of Toxoplasma gondii–Positive Subjects
Among All Controls Depending on Age.
Table 1. Serofrequency and Serointensity Between Diagnostic Groups and Controls (age > 45 y)
Titer < 16
Titer ? 128
Titer ? 16
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.
D. Hinze-Selch et al.
significant interrelationship with the TG antibody titer
We have presented the first controlled, age-adjusted,pro-
spective, large study of TG infection in psychiatric
patients with schizophrenia and major depression diag-
nosed 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 serointen-
sity (<1:16 vs 1:16–1:64 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 immu-
nologic or psychopathologic parameters revealed signif-
icant 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
ies with control groups matched by any means to the pa-
tient groups is low, ie, 4 of 23, of which 3 dealt with first-
episode 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 ur-
ban vs rural) for the likelihood of acquiring the infec-
tion.32We matched for both of these criteria, whereas
none of the previously published studies did so. From
our experience, controlling for age is essential. Slight dif-
ferencesin meanage, 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 de-
pression.Thus, wethink thatstudies that donotcarefully
adjust for age between groups must be considered with
caution. Furthermore, studies that report ‘‘increased an-
tibody levels’’ in patients must be carefully evaluated be-
cause 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
oftheserisk factors,buttheydiddifferwith respecttothe
interrelationship between these risk factors and seropos-
itivity: the eating of raw meat in the patients and risky cat
contact in the controls were associated with higher sero-
route, our patients might have eaten infected raw meat
more often, and the controls might have been hygieni-
cally 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
Table 2. Eating Habits in all Patients’ Groups and Risky Cat Contact in the Healthy Controls
Raw Meat ?
Raw Meat þ
Cat Contact ?
Cat Contact þ
Titer < 16
Titer ? 128
Titer ? 16
302 39 61 83 3961
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.
Table 3. CRP Values and Titer Categories in the Group
CRP < 6 [mg/l]
CRP ? 6 [mg/l]
Titer < 16
Titer ? 128
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.
Toxoplasma in Schizophrenia Beyond Seroprevalence
individuals older than 45 years. Moreover, the patients
with schizophrenia demonstrated significant interrela-
tionships between the titer category (serointensity) and
the course of the disorder as well as with inflammatory
variables and the use of immunomodulatory medica-
tions. Our results are consistent with previous studies
that found increased serotiters in first-episode patients
with schizophrenia.33,34As mentioned before, increased
serotiters are not necessarily in the range of the microbi-
ologically high titers suggestive of recent infection and,
therefore, might rather support the more intense anti-
body response of the host.35Consequently, 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 litera-
ture on immunologic peculiarities in individuals with
schizophrenia.1,36–40In the light of TG infection, these
data are of special interest.1,36As mentioned previously,
one basic host defense strategy is through proinflamma-
tory T-helper lymphocytes, ie, TH1 cells.12,13It was de-
scribed that individuals with schizophrenia with acute
symptomatology display increased TH1-associated cyto-
kine responses, returning to control levels during success-
ful antipsychotic treatment.41Therefore, an infection
such as TG might recurrently induce a TH1 response
that modulates the serotonin and dopamine neurotrans-
mitter systems, leading to respective psychotic symptom-
atology. Antipsychotic treatment that reorganizes these
neurotransmitter systems reduces the symptoms by mod-
ulating this common final pathway. Immunomodulating
antipsychotics28,37,42in addition might become involved
in the host defense against this infection. We found that
the use of immunomodulating antipsychotics was associ-
ated 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 re-
sponse 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 indi-
viduals with schizophrenia are associated with increased
TH1 activation; it might also provide an explanation for
the diverse findings in schizophrenia on the overactiva-
tion of TH1 or TH2 cytokines (for review of the TH2
hypothesis of schizophrenia see Schwarz39).
Table 4. Serointensity and Clinical Course in the Group ‘‘Schizophrenia’’
Titer < 16
Titer ? 128
Titer ? 16
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.
Table 5. Use ofAntidepressants andTiter Categoryin the Group
Titer < 16
Titer ? 128
Titer ? 16
242 49\4719\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 TCA’s; 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.
Table 6. Use of Immunomodulatory Medication and Titer
Category in the Group ‘‘Major Depression’’
Titer < 16
Titer ? 128
Titer ? 16
242 45\4422\67 34\57
Note: Chi-square test on the interrelationships between the use
of immunomodulatory medication (IM? = no, IMþ = 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.
D. Hinze-Selch et al.
We found high TG titers in first-episode patients 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 anti-
psychotics from the first episode onward. On the other
hand, because the high titers were seen in both first-
episode and chronic-course patients, continuously high
proinflammatory immune response to properly control
TG microcysts could be counterproductive. One can
speculate whether modulating this intense immune re-
sponse 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
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 re-
sponse that leads to dysregulated serotonin and
psychiatric symptoms, and perhaps even to the precipita-
tion of schizophrenia in vulnerable subjects,43then a spe-
cific and effective treatment of this infection, coupled
with a better understanding of how this vulnerability is
defined, will be mandatory.
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
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