Journal of Behavioral and Brain Science, 2011, 1, 47-56
doi:10.4236/jbbs.2011.12007 Published Online May 2011 (http://www.scirp.org/journal/jbbs)
The Infection Hypothesis of Schizophrenia:
A Systematic Review
Alexander M. Scharko
Rogers Memorial Hospital, Milwaukee, USA
Received February 19, 2011; revised March 25 , 2011; accepted M ar ch 28, 2011
Abstract
Objectives: The objective of this paper is to accomplish a systematic review of the infection hypothesis of
schizophrenia. Methods: All English language publications from January 1989 to March 2010 as related to
infection and schizophrenia were obtained. Each study selected for analysis must either deal with the direct
infection of an individual and schizophrenia or maternal infection during pregnancy and the subsequent de-
velopment of schizophrenia in the offspring. The primary outcome measure was the calculated odds ratio and
95% confidence interval (CI). Results: Over 300 titles and abstracts were reviewed. Eight retrospective
studies regarding in utero exposure were analyzed. Five nested case-controlled studies yielded an overall
odds ratio of 3.58 (95% CI: 2.71 - 4.71) with a percent attributable risk of 6.3%. Three Scandinavian popula-
tional studies yielded an overall odds ratio of 0.62 (95% CI: 0.49 - 0.79). Twenty-six papers were identified
as retrospective studies focused on linking evidence of past infection in individuals with history of schizo-
phrenia. A total of 77 microorganisms were assessed with 18 (23.4%) showing a positive association with
schizophrenia. But positive associations in a given trial were negative in other trials. Conclusions: Direct
infection of an individual as a cause of schizophrenia is unlikely. Results were mixed regarding maternal in-
fection, in utero exposure, and the later development of schizophrenia in the offspring and likely accounts for
a modest proportion of those with schizophrenia, possibly 6%.
Keywords: Infection Hypothesis, Schizophrenia
1. Introduction
The idea that a microorganism may be involved in the
pathophysiology of mental illness is not new. An edito-
rial contained in an 1896 issue of Scientific American
suggested that certain kinds of mental illness might be
due to infection (Scientific American 1896; 75: 303). In
1908, Chicago surgeon Bayard Taylor Holmes, believing
that focal infections, perh aps in the gastrointestinal tract,
induces a state of autointoxication that in turn causes
mental and physical illness, wro te, “It is my opinion that
there are many cases of insanity which are due to ex-
ogenous toxemia that should be sought for in the infec-
tion of some of the natural cavities of the body…” [1 ,2].
The neurodevelopmental model of schizophrenia pro-
poses that schizophrenia is the ultimate result of a per-
turbation in brain development that occurs long before
the manifestation of frank symptoms and that schizo-
phrenia is caused by a complex combination of genetic
and environmental factors th at are still poorly und erstood
[3,4]. It is possible that a two-step mechanism involving
(1) an internal genetic milieu that is permissive towards
schizophrenia along with an (2) external environmental
element(s) together provide the initial insult to neurode-
velopment that pushes the individual to develop schizo-
phrenia later in life. The environmental element in some
instances could be infection.
Since the first part of the 20th century, largely follow-
ing advances in molecular biology methods, mental
health researchers have attempted to identify microor-
ganisms that might be involved in the pathophysiology
of mental illness, specifically schizophrenia. Many mi-
croorganisms have been implicated (Table 1) including
viruses, bacteria, and at least one protozoan [5-7]. This
paper identifies, reviews, analyzes, and quantifies the
research on the infection hypothesis of schizophrenia. A
systematic review was performed. The results and con-
clusions are discussed in the framework of the neuro-

48 A. M. SCHARKO
Table 1. The infection hypothesis of schizophrenia - candidate microorganisms.
Viruses Bacteria Protozoan
Adenovirus 7Borrelia burgdorferi Toxoplasma gondii
Borna Disease Virus (BDV)Chlamydia trachomatis
Bovine Viral Diarrhea Virus (BVDV)Mycoplasma pneumoniae
Japanese Encephalitis Virus (JEV)
Cytomegalovirus (CMV)
Epstein-Barr Virus (EBV)
Herpes Simplex Virus-1 (HSV-1)
Herpes Simplex Virus-2 (HSV-2)
Human Herpes Virus-6 (HHV-6)
Varicella-Zoster Virus (VZV)
Influenza Virus
Measles Virus (Rubeola)
Mumps Virus
Human Parvovirus B19
Coxsackie Virus B5
Poliovirus
Reovirus
Human Immunodeficiency Virus (HIV)
Rubella Virus
developmental model of schizophrenia.
2. Methods
2.1. Search Strategy
All publications relevant to infection as it relates to
schizophrenia were obtained according to standard
guidelines [8]. The systematic review of the literature
was restricted to English language sources from January
1989 to March 2010. The bottom limit of January 1989
was chosen because it coincided with the introduction
and wide spread use of high quality polymerase chain
reaction (PCR) technique that could reliably detect pi-
comolar amounts of microorganism nucleic acid [9].
Electronic databases used were Cochrane Library, Med-
line, and PsycINFO. These online searches were aug-
mented by hand reviewing the reference lists of identi-
fied papers. All available studies, reviews, and reports
that mentioned some aspect of infection as it relates to
schizophrenia were considered. Any microorganism
mentioned as possibly being involved as causing
schizophrenia was cataloged and listed in Table 1.
The Cochrane Library search used the keyword
“schizophrenia.” A primary search of Medline and Psy-
cINFO used the keyword pairing of “schizophrenia” and
“infection.” A secondary search of Medline and Psy-
cINFO was done pairing the keyword “schizophrenia”
with the specific microorganisms in Table 1.
2.2. The Definition of Schizophrenia
For the purpose of this review, the diagnosis of schizo-
phrenia as defined by the authors of each study selected
for analysis was accepted.
2.3. Selection Criteria and Primary Outcome
Measure
In order to be included for analysis in this review, each
study must satisfy the following two selection factors:
1) Focus of a selected study must be either on the di-
rect infection of an individual and schizophrenia or ma-
ternal infection during pregnancy with subsequent de-
velopment of schizophrenia in the offspring.
2) Each selected study must contain sufficient data to
calculate an odds ratio.
The primary outcome measure is the calculated odds
ratio along with the 95% confidence interval. The odds
ratio was chosen because it is a statistic that estimates the
relative risk in case-controlled studies[10], which was
the study design anticipated to be encountered most fre-
quently. The od ds ratio and 95% confidence in terval (CI)
were calculated according to the method described by

A. M. SCHARKO
49
Dawson and Trapp [10]. Studies yielding positive or
negative results were included. Case reports and reviews
were used to augment the search process, but not used
for analysis. The search was not limited to any one spe-
cific microorganism.
2.4. Addressing Missing Data
For those studies that lent th emselves to yielding an odd s
ratio, but data within the paper were either incomplete or
absent, the principal investigator was contacted and
asked for those appropriate data in order to calculate
odds ratios.
2.5. Data Extraction and Analysis
Data from each study, review, and report were recorded
on a data extraction form. Information abstracted in-
cluded microorganism(s), study design, details regarding
method, and results. Studies eligible for analysis were
used to calculate an odds ratio. Homogeneity among
studies was determined by the results of graphically plot-
ting the proportion of those with schizophrenia onset in
the infection-exposed groups on the vertical axis and the
proportion of those with schizophrenia onset in the con-
trol groups on the horizontal axis. A linear trend was
assumed to indicate good homogeneity. Where appropri-
ate, numbers were combined to generate an overall odds
ratio and 95% confidence interval. Where appropriate,
the percent attributable risk, the percent of occurrence of
the disorder in those individuals exposed that is due to
the exposure, was then calculated [11].
3. Results
Over 300 titles and abstracts were reviewed. No prosp ec-
tive cohort studies were found with the specific aim of
following into adulthood the children of mothers with
documented infection during pregnancy and assessing
psychiatric status. No studies were found demonstrating
the development of schizophrenia in an individual sub-
sequent to an episode of infectio n.
With respect to indirect evidence linking infection and
schizophrenia, 13 papers were initially identified as be-
ing retrospective cohort studies focusing on maternal
infection during pregnancy and the later development of
schizophrenia in ad ult offspring [1 2-24]. All but two [1 7,
20] reported a positive association between infection and
the development of schizophrenia in the adult offspring.
Five studies were excluded because of missing data
[12,15,19,21,23]. The analysis for the remaining eight
studies is displayed in Table 2. A graphical assessment
(Figure 1) revealed reasonable homogeneity amongst the
first five nested case controlled studies. Thus those data
Table 2. Maternal infection, in utero exposure, and later development of schizophrenia in the offspring.
Study
Microorganism
or Medical
Condition Re-
lated to Infec-
tion
Basis for
Infection
Diagnosis
During Preg-
nancy
Number with
Schizophrenia
and Exposure
Number
without
Schizophrenia
and Exposure
Number with
Schizophrenia
and No Ex-
posure
Number
without
Schizophrenia
and No Ex-
posure
Odds
Ratio
95%
Confi-
dence
Interval
Brown et al.,
2006 [17] HSV-1/HSV-2 Serologically 16 24 55 86 1.04 0.48 - 2.26
Brown et al.,
2005 [16] Toxoplasma gondii Serologically 18 22 45 101 1.84 0.85 - 3.98
Brown et al.,
2004 [13] Influenza virus Serologically 22 37 85 163 1.14 0.61 - 2.14
Brown et al.,
2000 [18] Respiratory infections Clinically 9 623 49 7,100 2.09 0.96 - 4.44
Brown et al.,
2000 [14] Rubella virus Clinically 11 59 15* 1,511 18.78 7.67 - 45.66
Clarke et al.,
2009 [20] Pyelonephritis Finnish
Medical Reg-
istry 36 9,560 35 13,773 1.48
0.908 - 2.419
Mortensen
et al., 2007
[22]
Toxoplasma
gondii
Danish Medi-
cal Registry &
Biobank 17 68 54 616 2.85 1.50 - 5.39
Sorensen
et al., 2009
[24]
Bacterial
Infection
Copenhagen
Perinatal
Cohort 38 1,027 200 6,675 1.24 0.85 - 1.78
Combining
First Five
Studies 76 765 249 8,961 3.58 2.71 - 4.71
Combining
Population
Studies 91 10,655 289 21,064 0.62 0.49 - 0.79
* The number with schizophrenia and with no in utero exposure was estimated. Assuming a 1% prevalence of schizophrenia, then 1,511  0.01  15.

A. M. SCHARKO
50
Figure 1. Heterogenity determination.
from the first five studies were pooled. The overall odds
ratio from the first five studies showed an increased like-
lihood of schizophrenia among those exposed to mater-
nal infection while in utero (Overall Odds Ratio = 3.58;
95% CI: 2.71 - 4.71) with a percent attributable risk of
6.3%. Given the use of Scandinavian national databases,
the population studies were assumed to be homogeneous
and were combined. The three population studies yielded
an overall odds ratio that suggested no increased likeli-
hood of schizophrenia among those exposed to maternal
infection while in utero (Overall Odds Ratio = 0.62; 95%
CI: 0.49 - 0.79).
Another 26 published retrospective cohort studies at-
tempted to link evidence of past infection with schizo-
phrenia [25-50] (i.e., direct exposure to infection). Sam-
ples ranged from post-mortem brain tissue to blood from
patients and controls. Standard molecular biology tech-
niques were used such as enzyme linked immunosorbent
assay (ELISA), Western blot, and polymerase chain re-
action (PCR). Frequently, multiple microorganisms were
assessed in a given study. Taking each microorganism
investigated as a separate trial, 23.4% of trials yielded a
positive association (18 out of 77 trials; Table 3).
The 18 separate trials were published in 16 papers [27,
28,31,32,34-39,41-43,47,49,50]. Five trials from four
papers were excluded because of missing data [27,36,
39,42]. Two positive trials focusing on other issues in-
stead of infection causing schizophrenia were also ex-
cluded [31,32]. Eleven trials were included in the analy-
sis (Table 4). A graphical assessment (Figure 2) re-
vealed poor homogeneity amongst these 11 trials. Thus
individual odds ratios were calculated for each of the 11
eligible trials and presented in Table 4. No overall odds
ratio was calculated because homogeneity could not be
assumed. One of those 11 trials contained zero in the
odds ratio calculation [35], but still was listed in Tab l e 4 .
Two separate studies seemed to use identical data [36,37] .
Five studies were found that specifically investigated
CNS infection occurring during childhood and the later
development of schizophrenia [51-55]. Although all five
studies showed a positive association between childhood
CNS infection and the later development of schizophre-
nia, the possibility of infection-induced brain damage
resulting in schizophrenia-like psychiatric symptoms
could not be ruled out. Thus, these studies were not in-
cluded for anal y s i s.
Table 3. Evidence of past infection and history of schizophrenia - microorganisms investigated and outcome (77 total trials).
Microorganism Number of Positive As sociations
with Schizophrenia Number of Negative Associations with Schizophrenia
Borna Disease Virus (BDV) 7 (9.1%) 3 (3.9%)
Bovine Viral Diarrhea Virus (BVDV) 0 1 (1.3%)
Japanese Encephalitis Virus (JEV) 0 1 (1.3%)
Cytomegalovirus (CMV) 2 (2.6%) 8 (10.4%)
Epstein-Barr Virus (EBV) 0 8 (10.4%)
Herpes Simplex Virus-1 (HSV-1) 1 (1.3%) 6 (7.8%)
Herpes Simplex Virus-2 (HSV-2) 0 5 (6.5%)
Human Herpes Virus-6 (HHV-6) 1 (1.3%) 6 (7.8%)
Varicella-Zoster Virus (VZV) 0 8 (10.4%)
Influenza Virus 0 5 (6.5%)
Measles Virus (Rubeola) 0 2 (2.6%)
Mumps Virus 0 2 (2.6%)
Retrovirus 2 (2.6%) 1 (1.3%)
Human Immunodeficiency Virus (HIV) 0 1 (1.3%)
Rubella Virus 0 1 (1.3%)
Toxoplasma gondii 5 (6.5%) 1 (1.3%)
Totals 18 (23.4%) 59 (76.6%)

A. M. SCHARKO
51
Table 4. History of direct infection in individuals and the development of schizophrenia*.
Study Microor-
ganism
Number with
Schizophrenia
and Exposure
Number without
Schizophrenia
and Exposure
Number with
Schizophrenia
and No Exposure
Number without
Schizophrenia
and No Exposure
Odds
Ratio 95% Confidence Interval
Nunes et al.,
2008 [43] BDV 12 4 15 23 4.60 1.08 - 21.09
Chen et al.,
1999 [28] BDV 38 32 276 459 1.97 1.17 - 3.33
Iwahashi
et al.,
1998 [37] BDV 30 1 37 30 24.32 3.21 - 513.30
Iwahashi
et al.,
1998 [36] BDV 30 1 37 30 24.32 3.21 - 513.30
Iwahashi
et al.,
1997 [35] BDV 30 0 37 26 NA NA
Waltrip II
et al.,
1995 [49] BDV 15 3 75 17 1.13 0.26 - 5.55
Hart et al.,
1999 [34] Retrovirus 29 4 38 12 2.29 0.60 - 9.46
Lillehoj et al.,
2000 [40] Retrovirus 11 1 27 26 10.60 1.24 - 238.79
Niebuhr
et al.,
2008 [41]
Toxoplasma
gondii 15 37 165 491 1.21 0.62 - 2.34
Tamer et al.,
2008 [47] Toxoplasma
gondii 16 6 24 31 3.44 1.05 - 11.73
Yolken
et al.,
2001 [50]
Toxoplasma
gondii 14 3 24 24 4.67 1.05 - 23.04
* BDV = Borna Disease Virus, NA = Not Applicable.
4. Discussion
Edwin Goodall, a President of the Section of Psychiatry
in the British Royal Society of Medicine, lecturing in
Figure 2. Heterogenity determination.
1932, stated, “…there is no essential difference con-
nected with encephalitis (post-encephalitic) and those
met within states covered by the description schizophre-
nia” [56]. Goodall went on to speculate, “…that a virus
or toxin is the causative factor…vaccina, varicella, vari-
ola, measles, perhaps influenza.” Following Goodall’s
lead, it was later observed that there appears to be a 5%
to 8% excess of late winter and early spring births of
individuals who later in life develop schizophrenia [57].
This season-of-birth effect implied that maternal infec-
tion during pregnancy might be a factor in causing
schizophrenia in the offspring. Further, data extrapolated
from the analysis of ecological events, mostly the influ-
enza pandemics, have linked prenatal exposures to infec-
tious agents to the risk of developing schizophrenia later
in life [58-69], although not all of those ecological stud-
ies showed a positive association [70-75]. In a review of
prenatal infection and schizophrenia published in March
2010 Brown and Derkits [76] contend that of those indi-
viduals with schizophrenia perhaps as many as 30%
could have been prevented if certain infections could
have been avoided among pregnant women. The idea
that infection is involved in the pathophysiology of
schizophrenia simply will not go away.

52 A. M. SCHARKO
Although direct in fection of an individual can produ ce
psychiatric symptoms that look like schizophrenia
[77,78], three findings in this review argue against direct
infection and the subsequent development of schizophre-
nia. First, as indicated in Table 3, there was essentially
no consistency across studies as 76.6% of the possible
associations were negative. Further, those microorgan-
isms that produced positive associations in some trials
also produced negative associations in other trials. Sec-
ond, appropriate temporal sequencing was a concern
because it was unclear precisely when infection occurred
with respect to the onset of schizophrenia. It is known
that about 75% of those individuals with schizophrenia
also have a co-occurring physical health problem such as
heart disease, cancer, or diabetes [79]. It then would not
be unusual to find evidence of past infection by a variety
of microorganisms in this population. Third, of those
studies in which an odds ratio could be derived (Table 4),
three contained one in the 95% confidence interval cal-
culation. Another three had exceedingly wide confidence
intervals. These statistical results call into question
whether a true association actually exists. Finally, it is
more biologically plausible that schizophrenia is a neu-
rodevelopmental disorder and not the sequela of acute
infection. An infection process that precipitates psycho tic
symptoms is better characterized as delirium or psycho-
sis due to a medical condition as opposed to schizophre-
nia. Taken together, these findings suggest it is unlikely
that direct infection of an individual is a cause of
schizophrenia.
Table 2 shows mixed evidence regarding maternal in-
fection during pregnancy and the later development of
schizophrenia in the offspring. The first five studies are
unique in that each study was a nested case controlled
design that drew upon well-defined populations and each
of the five studies were done by the same research group.
Overall, the findings suggested a 3.58 (95% CI: 2.71 -
4.71) greater risk of later development of schizophrenia
in offspring with in utero exposure to a microorganism,
and/or the products and consequences of infection, than
in those without such exposure. This in utero effect may
account for up to 6% of cases of schizophrenia. These
results stand in contrast to the three Scandinavian popu-
lational studies that actually indicate a protective effect
with respect to maternal infection with an overall odds
ratio of 0.62 (95% CI: 0.49 - 0.79). If those data across
all of the studies in Table 2 were combined the odds ratio
becomes 0.82 with a 95% confidence interval of 0.68 to
0.98; perilously close to one and implying that maternal
infection is not a major cause of schizophrenia in the
offspring.
Microorganisms and humans evolved together. It is no
surprise that there exists many connections, overlaps, and
interactions between microorganisms and human physic-
ological chemistry [80]. One might consider evoking the
hygiene hypothesis [81] and say that a certain amount of
maternal infection or microbial colonization is tolerated,
perhaps even required, during pregnancy. But, it may be
that once a critical inflection point is reached with re-
spect to microbial involvement, fetal and/or maternal
tolerances may be breached thus placing the developing
fetal nervous system at some degree of risk. An explana-
tion that fits with the neurodevelopmental model of
schizophrenia is that microbial gene products that mimic
host cytokines (such as virokines [82,83] or other
pseudo-cytokines from bacteria or protozoans) and/or the
generation of pro-inflammatory cytokines [84,85] may
perturb fetal neurodevelopment in a subtle, but signifi-
cant way that later results in the development of schizo-
phrenia. At what neuro-location within the fetus and at
what moment of development is most vulnerable are
unknown, but stochastic factors are likely involved.
Unfortunately, nothing was said about the fathers of
those offspring who later went on to develop schizophre-
nia. There is reason to believ e that older paternal age is a
risk factor for the later development of schizophrenia in
the offspring [86]. Paternal age then was a possible con-
founding factor in those studies focusing on maternal
infection. Finally, none of the studies surveyed for this
review could account for the lack of increase in preva-
lence of schizophrenia in those areas of the world where
infectious disease is prominent [87]. There is evidence
that schizophrenia is more prevalent in the developed
countries where one would think that public health
measures and infection control would be the best[88].
Thus, in utero exposure to a microorganism, and/or the
products or consequences of infection, as a cause of
schizophrenia - although a good example of gene/envi-
ronment interaction [80,89] and consistent with the neu-
rodevelopmental model of schizophrenia - may only ac-
count for a modest proportion of those individuals with
schizophre ni a , perhaps 6%.
This systematic review has several limitations. First, it
only contained studies that were published after January
1989. Unpublished reports and studies in languages other
than English were not collected. Thus not every study
regarding infection and schizophrenia was evaluated in
the formal analysis. Second, the problem of missing data
was difficult to overcome. Therefore several studies
needed to be excluded from formal analysis. Third, ho-
mogeneity was a major problem for those studies at-
tempting to relate direct infection in an individual and
the subsequent development of schizophrenia (Table 4).
This precluded combining odds ratio data in any
straightforward way. Fourth, the definition of schizo-
phrenia varied from study to study. It frequently was

A. M. SCHARKO
53
difficult to differentiate a valid diagnosis of schizophre-
nia from a medical condition manifesting with schizo-
phrenia-like symptoms, such as delirium or psychosis
due to a medical condition.
5. Acknowledgements
Susan dosReis, PhD Assistant Professor, Division of
Child and Adolescent Psychiatry, Johns Hopkins Uni-
versity School of Medicine, Baltimore, MD, provided
valuable comments and statistical consultation. David C.
Lee, PhD, JD, Director of Psychology and Research,
Mendota Mental Health Institute, Madison, WI, kindly
edited an earlier version of this review.
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