Molecular Psychiatry (2008) 13, 470–479
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PERSPECTIVE
Are some cases of psychosis caused by microbial agents?
A review of the evidence
RH Yolken1 and EF Torrey2
1
The Stanley Laboratory of Developmental Neurovirology, Department of Pediatrics, Johns Hopkins University Medical Center,
Baltimore, MD, USA and 2The Stanley Medical Research Institute, Chevy Chase, MD, USA
The infectious theory of psychosis, prominent early in the twentieth century, has recently
received renewed scientific support. Evidence has accumulated that schizophrenia and bipolar
disorder are complex diseases in which many predisposing genes interact with one or more
environmental agents to cause symptoms. The protozoan Toxoplasma gondii and cytomegalovirus are discussed as examples of infectious agents that have been linked to schizophrenia
and in which genes and infectious agents interact. Such infections may occur early in life and
are thus consistent with neurodevelopmental as well as genetic theories of psychosis. The
outstanding questions regarding infectious theories concern timing and causality. Attempts
are underway to address the former by examining sera of individuals prior to the onset of
illness and to address the latter by using antiinfective medications to treat individuals with
psychosis. The identification of infectious agents associated with the etiopathogenesis of
schizophrenia might lead to new methods for the diagnosis, treatment and prevention of this
disorder.
Molecular Psychiatry (2008) 13, 470–479; doi:10.1038/mp.2008.5; published online 12 February 2008
Keywords: cytomegalovirus; toxoplasmosis; infectious; schizophrenia; genetic; environmental
Introduction
The idea that microbial agents may cause psychotic
disorders has a surprisingly lengthy history. As the
germ theory of diseases became established in the
late-nineteenth century, several European researchers
theorized that bacteria might be etiologically linked to
dementia praecox or other psychiatric diseases. It was
speculated at that time that the bacteria might not
infect the brain directly but rather could reside in the
intestine or elsewhere and, by a process of autointoxication, affect the brain by secreting toxins.
One of the earliest enthusiasts for this theory was
Emil Kraepelin who, in the 1896 edition of his
Psychiatrie, reasoned that dementia praecox was ‘a
tangible morbid process of the brain’ caused by ‘an
autointoxication whose immediate causes lie somewhere in the body’; Kraepelin believed that the sex
organs were the most likely site of infection.1 The fact
that psychoses occasionally accompanied known
bacterial diseases such as typhoid fever, tuberculosis
and diphtheria supported the infectious theory; a 1904
review concluded that although ‘insanity following
infection is generally of short duration, y in a few
Correspondence: Dr RH Yolken, The Stanley Laboratory of
Developmental Neurovirology, Department of Pediatrics, Johns
Hopkins University Medical Center, 600 N Wolfe Street, 1105
Blalock, Baltimore, MD 21287-4933, USA.
E-mail: [email protected]
Received 21 March 2007; revised 14 June 2007; accepted 26 June
2007; published online 12 February 2008
cases it does last from several months to years’.2 The
following year, a spirochete was discovered to be the
cause of syphilis, and by the First World War,
infectious theories had joined genetic and endocrine
theories in the mainstream of psychiatric research.
The autointoxication theory, however, fell into
disrepute following attempts by several researchers
to surgically remove the theoretical foci of infection in
various organs, often with tragic results.3,4 Attention
then shifted to viruses, after it was noted that
infection with the influenza virus caused psychosis
in some people.5 Such cases were extensively studied
by Karl Menninger following the 1918–1919 influenza
pandemic. After observing many cases, Menninger
concluded: ‘I am persuaded that dementia praecox
(schizophrenia) is at least in most instances a somatapsychosis; the psychic manifestations of an encephalitis (italics in original). The acuteness or chronicity,
the benign or malignant nature of this encephalitis
perhaps determines the degree of reversibility of the
schizophrenia.’6 In recent years, modern imaging
techniques have established that schizophrenia is,
in most cases, not associated with acute encephalitis,
although it remains possible that it is a sequela or
recurrence of a past episode of encephalitis.
Interest in infectious theories of psychiatric disorders waned in the United States and Europe in
the 1930s as Freudian theories became prominent.
Psychiatric research on infectious agents continued
sporadically, mostly in Eastern Europe7,8 and Russia,9
but after the onset of the Cold War, these studies were
Psychosis and microbial agents
RH Yolken and EF Torrey
not widely known in the West. In the 1970s, there was
renewed interest in infectious agents in Western
Europe10–12 and the United States,13,14 culminating
in a 1983 World Health Organization symposium,
‘Research on the Viral Hypothesis of Mental Disorders’.15 Since that time, interest in this research area
has steadily increased.
This review attempts to summarize such research.
It first summarizes general evidence favoring an
infectious theory, and then discusses the interaction
of microbial agents and genetic factors. Of necessity,
the review does not discuss every infectious agent
and every psychiatric disorder that have been
studied. It rather focuses on psychotic disorders
in general, and schizophrenia in particular, as
examples, and on the infectious agents that appear
to be the most promising etiological candidates:
Toxoplasma gondii and cytomegalovirus (CMV).
Finally, it concludes with a summary of the current
state of this research area, including both its strengths
and weaknesses.
Why should microbial agents be considered?
There are several aspects of psychotic disorders that
suggest a possible infectious origin. One is the centuryold observation, noted above, that individuals
sometimes present with the clinical symptoms of
schizophrenia, bipolar disorder or depression with
psychosis in the course of developing, or shortly after
having had, a known microbial disease. The list of
infectious agents that have been reported to sporadically cause psychotic symptoms is long but most
prominently includes spirochetes such as Treponema
pallidum (causing syphilis) and Borrelia burgdorferi
(causing Lyme disease); viruses such as herpes simplex
viruses (HSV-1 and -2), Epstein–Barr virus, CMV,
influenza, measles, rubella, mumps, polio, vaccinia,
enteroviruses such as Coxsackie B4, arboviruses such
as Eastern equine encephalitis virus, retroviruses such
as the human immunodeficiency virus (HIV) or
endogenous human retroviruses, and Borna disease
virus; and protozoa such as T. gondii.16–18 Such cases
may become evident by the appearance of neurological
symptoms shortly after the onset of psychotic symptoms, or they may remain hidden until autopsy.
Epidemiological considerations, however, make it
unlikely that many of these microbes are candidates
for causing a large number of cases of schizophrenia
or other psychoses. Since psychoses are widespread
in the world, localized infectious agents such as
arboviruses, Borna disease virus and B. burgdorferi
are unlikely to be causative agents in different areas of
the world. Schizophrenia and bipolar disorder have
also been described for at least 200 years, thus ruling
out infectious agents that only recently infected
human populations, such as HIV. In addition, the
incidence of schizophrenia and bipolar disorder has
not decreased markedly in recent years, whereas the
incidence of syphilis, rubella, measles and mumps
has done so as a result of immunization and improved
therapies. Thus, relatively few microbes meet epidemiological requirements for serious consideration for
causing more than sporadic cases.
Another epidemiological aspect of schizophrenia
and bipolar disorder is the fact that both have a
modest seasonal birth predominance in the winter
and spring months.19 Over 200 studies have demonstrated this, and it is, in fact, one of the most
consistently replicated aspects of these disorders.
Statistical artifact and parental procreational habits
have been ruled out as explanations, but seasonal
differences in sunlight, temperature, rainfall, birth
complications, toxins and nutrition have all been
considered, along with microbes. If an infectious
agent is responsible for the seasonality, it would be
one that occurs through the year but that has a modest
seasonal predominance. The infectious agent would
also be one that does not vary markedly in incidence
from year to year; this makes influenza an unlikely
candidate.
Another epidemiological fact of interest is that
being born in, or raised in, an urban environment,
compared to a rural environment, approximately
doubles a person’s risk of later being diagnosed with
schizophrenia. The urban risk is clearly associated
with schizophrenia but has not been observed for
bipolar disorder or other affective disorders.20 A
dose–response relationship has been described insofar as ‘the more years lived in the higher degree of
urbanization, the greater the risk’.21 In one study, the
population-attributable risk for developing schizophrenia due to childhood urban living was 34.6, more
than six times greater than the genetic risk conferred
by having a first-degree relative with schizophrenia
(5.5).22 Socioeconomic status and obstetric complications have been ruled out as explanations of the urban
risk factor;23 a greater density of population must be
considered, since it is associated with the rapid
transmission of many microbes.
An unresolved issue concerning the possible
microbial etiology of psychosis is the timing of the
infection. In some, but not all, studies, it has been
reported that maternal infections with rubella,24
influenza,25 HSV-226 and T. gondii 27,28 increase the
incidence of psychotic disorders in the offspring.
Other studies have documented an increased rate of
schizophrenia in adults who during childhood had
viral or bacterial meningitis.29 It is thus possible that
microbes could cause psychosis secondary to infections in utero, in infancy or in childhood in addition
to in adulthood around the time of onset of the
psychosis. It is also possible that an infection
occurring in infancy can be reactivated in later life,
as is known to occur with the herpes viruses and
T. gondii. The outcome of the infection may differ
markedly depending on its timing, as is known to be
true for human infections such as those caused by the
rubella and polio viruses. It is also known that
infections at different stages of brain development
result in varying degrees of lifelong changes in
behavior and cognition.
471
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RH Yolken and EF Torrey
472
How genes and microbes interact
Despite more than a century of research, the genetic
basis of psychotic disorders is not well understood.
For schizophrenia, recent research has focused on the
search for genetic mutations and polymorphisms as
causes. This research is based on multiple family
studies indicating that schizophrenia has a high
degree of heritability; it has been stimulated by the
wealth of genetic information that has become
available as part of the human genome project.
The search for specific genes associated with schizophrenia has also been fueled by findings from linkage
studies indicating that some regions of the human
genome are inherited nonrandomly in family members who have schizophrenia.
Despite a great deal of laboratory research, no single
gene has been discovered that has a major effect in
different populations. Although several genes have
been associated with schizophrenia in case-control
and family studies, many have not been found to be
operant in different populations. The genes that are
consistently associated with schizophrenia in different studies have relatively low odds ratios, generally
in the range of 1.1–1.5. Studies reporting higher odds
ratios have generally not been reproducible in subsequent studies performed in other populations. An
increased understanding of human haplotype structure has also suggested that the strength of some
previously reported associations has been overestimated because of haplotype misclassification. In
addition, many of the genes that are associated with
schizophrenia have similar associations with other
psychiatric disorders such as bipolar disorder and
unipolar depression, as has recently been described
for methylenetetrahydrofolate reductase.30
While the reproducible associations are of great
interest to neurobiologists interested in elucidating
pathways of neural transmission and other neurological processes, associations at this level are of
substantially less value to clinicians and epidemiologists, since they have low positive predictive values
and thus provide little in the way of clinical or
diagnostic guidance. Furthermore, findings in this
range are difficult to duplicate except in studies of
large sample sizes. For example, it takes a study of
approximately 2000 individuals to detect a genetic
factor that is present in the general population at
a rate of 10% and that has a relative risk of 1.5 with a
power of 0.9. Even larger sample sizes are required to
detect genes that are present in lower prevalence or
that have lower odds ratios; for example, more than
6100 individuals would be required to detect a gene
with a population prevalence of 5% and a relative risk
of 1.4.
Methods for genetic analysis are continually evolving. There is currently much interest in methods that
can increase the number of genetic loci that can be
evaluated in a given period of time. While such
methods, which include ‘whole genome association’
studies, have given hope in terms of finding new
Molecular Psychiatry
areas of genetic association, it is difficult to envision
how the results from these studies will solve the
problem of the low odds ratios and the population
diversity that seem to be inherent in the study of
schizophrenia. In fact, it can be anticipated that these
studies will result in the identification of larger
numbers of potential genetic associations that will
need to be replicated in very large sample sizes and
then integrated into current algorithms. Furthermore,
the analyses of larger numbers of potential loci will
require the performance of larger numbers of multiple
comparisons among genes, making it even more
difficult to distinguish positive findings from true
associations.
For this reason, it is important to elucidate
nongenetic factors that might contribute to schizophrenia. Of particular importance are environmental
influences that might interact with genetic factors and
thus be applicable to a disease such as schizophrenia,
which has a high degree of heritability. The integration of environmental risks might increase the odds
ratios of genetic associations in specific populations
of exposed individuals and hence increase the likelihood of identifying true positive associations.
The modern era of studying how genes and
microbes interact was initiated in 1948 with the
observation by Haldane31 that the gene for sickle
hemoglobin provides protection against malaria,
undoubtedly explaining the persistence of this gene
in humans living in malaria endemic areas. More
recently, the observation that individuals vary in their
response to HIV infection has led to the discovery of a
number of genes that are associated with a variable
response to retrovirus infection. There are many
additional infectious diseases for which a genetic
component has been found in repeated studies. These
include infections caused by Mycobacterium tuberculosis, M. leprae (leprosy), hepatitis B and C viruses,
cholera, Helicobacter pylori, norovirus and Leishmania donovani. In addition, genes are very important in
infectious diseases involving multiple organisms,
such as bacterial sepsis and otitis media.32
Currently recognized genetic determinants of
response to infection include receptors, transcription
factors, cytokines, complement components, human
lymphocyte antigen and other T-cell determinants,
Toll-like receptors and other determinants of innate
immunity. As different aspects of the immune system
are more precisely defined in humans and in animal
models, there is an ever-increasing list of genes that
can potentially be associated with host response to
infectious agents. In addition, the receptors for
specific agents are being increasingly identified
through the application of molecular biological
techniques, further increasing the number of potential
genetic loci defining susceptibility to infectious
agents.
As discussed above, there are a number of infectious agents, which have been associated with
schizophrenia. This review focuses on Toxoplasma
and CMV, since they meet the criteria discussed above
Psychosis and microbial agents
RH Yolken and EF Torrey
and have been associated with schizophrenia in
different populations
T. gondii and schizophrenia
T. gondii is a coccidian protozoan of the apicomplexa
family, first described in 1908. Felines, including
domestic cats, are its definitive host, and the organism can only complete the sexual part of its life cycle
within feline hosts. As shown in Figure 1, T. gondii
oocysts are excreted in the feces of cats at the time
they are initially infected. The oocysts may then
become aerosolized and infect humans who are
changing cat litter boxes, gardening or playing in
sandboxes. The cat may also deposit feces on the
ground or in animal feed in barns; domestic animals
may eat it, producing T. gondii tissue cysts in their
muscles, which then infect humans who eat undercooked meat. Felines can also contaminate water,
with subsequent infection of humans through drinking water, eating vegetables washed with contaminated water or eating undercooked fish that had lived
in the contaminated water. The relative importance of
different modes of transmission depends upon local
geographic, cultural and socioeconomic factors.
T. gondii is distributed worldwide and infects
between 10 and 80% of the adult population; in the
United States, the rate is approximately 25%.33 Of
interest in relationship to schizophrenia, the peak
ages of seroconversion is between ages 15 and 35;34
adolescent males become infected earlier than
females35 and there are inconsistent suggestions of a
seasonal occurrence (least in summer)36,37 and greater
urban risk.38
Genetically, numerous animal studies have identified genetic determinants of response to T. gondii
infection, especially in immune-compromised hosts.
Host genes associated with susceptibility or resistance
to Toxoplasma infections include ones that regulate the
expression of T-cell determinants,39 nuclear factor-kB
transcription,40 interferon gamma,41 lymphotoxina,42
other cytokines,43 Toll-like receptors44 and chemokine
receptors,45 as well as genes of an as yet undefined
effect on macrophage function.46 The genes that
determine the response to Toxoplasma in immune
competent humans have not yet been defined but are
the subject of ongoing investigations.
Clinically, most human infections with T. gondii had
been thought to be asymptomatic. However, recent
studies of individuals infected with Toxoplasmacontaminated water have indicated that a majority of
infected immune-competent individuals have clinically apparent symptoms, such as headache, fever,
malaise, myalgias, adenitis, anorexia and arthralgias.47
473
Oocysts deposited in many places
KITTYLITTER
The ground
Animal feed in barn
Water supply
Gardensands and boxes
Eaten by animals
Pregnant
woman
inhales
oocysts
Fetus is affected
(congenital
toxoplasmosis)
Figure 1
Washed
vegetables and
fish are
contaminated
People eat
undercooked
meat
People work
in gardens,
play in
sandboxes
Eaten by mice and
rats, whose
behavior may be
altered by the
Toxoplasma, making
them easier prey
Theyare then
eaten by other
cats, beginning
another cycle
Life cycle of T. gondii.
Molecular Psychiatry
Psychosis and microbial agents
RH Yolken and EF Torrey
474
Occasional cases have been described with delusions
and hallucinations.48 The microbe is known to be
neurotrophic and to infect both neurons and glia.49
Serologically, the first research linking schizophrenia
and other psychoses to an increase in antibodies to
T. gondii was published in 1953; since then, at least
41 other studies have been carried out. A recent
meta-analysis on 23 of these studies reported an odds
ratio for schizophrenia risk associated with serological evidence of T. gondii infection as 2.73 (95%
confidence interval, 2.10–3.60; P < 0.000001).50 While
still in the range of moderate association, this odds
ratio is substantially higher than that found in most
meta-analyses of specific genes associated with schizophrenia risk.
These serological findings are supported by other
studies linking T. gondii to schizophrenia. A study
of newborn sera and a study of maternal sera of
individuals who later developed schizophrenia and
schizophrenia spectrum disorders both reported more
T. gondii antibodies in cases than in controls.27,28 In
addition, preliminary analysis of a cohort of individuals in the US Military indicates that increased
levels of Toxoplasma antibodies can be found in
individuals prior to the onset of symptoms, obviating
the possibility that the finding of increased levels of
antibodies is an epiphenomenon associated with
exposure occurring after the onset of disease.51
There are a number of reasons why interest in the
study of the role of Toxoplasma and other infectious
agents in the etiology of schizophrenia has, until
recently, been limited to a small number of investigators. First, until recently, there was little understanding of the molecular biology of T. gondii and the
pathophysiological mechanisms by which Toxoplasma
infection causes disease. Recently, the techniques that
led to the sequencing of the human genome have been
applied to the sequencing of protozoan genomes as
well, resulting in a corresponding increase in the
characterization and understanding of the molecular
basis of infection. For example, the characterization of
the genome of T. gondii, which was completed in 2005,
has led to an increased understanding of the biology of
Toxoplasma infections and to the development of
assays for antibodies to specific Toxoplasma proteins.
The application of these assays has revealed that
Toxoplasma organisms, which had previously been
thought to be relatively uniform in terms of biological
properties, exist in multiple strains with differing
degrees of pathogenicity. Of particular importance has
been the recent elucidation of specific Toxoplasma
protein kinases in some strains, which alter signal
transduction in infected hosts and thus modulate
humoral immune function. These protein kinases
appear to be the major determinants of the pathogenicity of individual Toxoplasma strains.52,53 Further
studies of these and other markers of pathogenicity
should lead to improved assays for defining the risk of
disease in Toxoplasma-infected individuals.
Another factor that has impeded an understanding
of the role of infectious agents as etiological factors in
Molecular Psychiatry
schizophrenia has been the lack of a teleological
framework relating to why, from an evolutionary
point of view, infection with a microbial agent might
lead to the altered behavior that is the hallmark of
schizophrenia. However, recently it has been recognized that infectious agents can alter host behavior in
a manner than enhances the survival and reproduction of the infecting agent. T. gondii provides a prime
example of this type of evolutionary adaptation. As
noted above, felines constitute the natural hosts for
the protozoan. If a Toxoplasma organism infects a cat
or other member of this family, it can complete its
entire life cycle, including sexual reproduction. If,
however, the organism infects another animal, for
example, through the ingestion of Toxoplasma organisms shed by infected cats, the non-feline host is a
‘dead end’ for the Toxoplasma, in that the microbe
cannot complete the sexual part of its life cycle and
thus remains trapped in cyst form within the tissues
of this incomplete host. The organism trapped in a
non-feline host has another way out, however; if it
can get the host to be eaten by a feline, it will be able
to complete its life cycle in the new feline host.
Since all felines are carnivores, the possibility that
another animal will be consumed is not remote; if the
host is a rodent or other small animal, the possibility
is even greater. Recent research has indicated that
T. gondii can increase the likelihood of having its
rodent intermediate host eaten by a cat by altering the
motor behavior of the rodent.54 Specifically, the
rodent loses its inherent fear of novel stimuli,
including its fear of cats. Behavioral experiments
have documented that Toxoplasma-infected rats lose
their aversion to cat urine without other alterations in
motor behavior, such as lethargy, which might make
the rat less desirable prey to felines. In the real world,
this alteration is likely to lead to a markedly increased
consumption of Toxoplasma-infected rodents by cats,
resulting in an infection of the cats and completion of
the Toxoplasma life cycle. Since humans are generally not liable to be consumed by felines (hunters and
trainers of large cats excepted), the effect of Toxoplasma on humans is largely vestigial. Since the
Toxoplasma organism has limited ability to modulate
its response in different intermediate hosts, however,
it can be postulated that all hosts can be affected by
similar pathways. In fact, in humans, two studies
have independently reported that young adults with
serological evidence of Toxoplasma infection have
increased rates of automobile accidents compared to
age-and gender-matched controls, a behavior that is
likely to be associated with increased risk-taking
behavior.55,56
The neurobiological mechanism by which T. gondii
causes psychiatric symptoms and exerts its effect on
human behavior is unknown. One possibility is a
direct effect of the organism on neurons and/or glia;
such an effect may occur at the time of infection or
much earlier in life. There are animal models of
infections known to occur in utero or early in life that
do not become manifest with behavioral changes until
Psychosis and microbial agents
RH Yolken and EF Torrey
the animal reaches maturity.57 In the case of T. gondii,
it is known that the organism may affect signal
transduction pathways and that it also encodes
proteins with hemology to tyrosine hydroxylase
and the mammalian D2 receptor, suggesting that it
may interfere with dopamine synthesis pathways in
human hosts.58,59 There are also models of infectious
agents that affect dopamine pathways in one part of
the brain but not in others.60 Alternatively, infectious
agents such as T. gondii may cause psychiatric
symptoms by the effect of antibodies against the
organism or by cytokines elicited by the infection.61
Studies of such mechanisms are ongoing.
The development of hallucinations and other
clinical symptoms in an individual infected with
Toxoplasma is thus likely to be dependent on both the
human and the microbial genomes. In this sense,
schizophrenia might be considered not merely a
genetic disease but rather a disease resulting from
the interaction of multiple genomes. In this context, it
is likely that study of both the human and the
microbial genomes will be required to come to a
complete understanding of complex neuropsychiatric
disorders such as schizophrenia.
Cytomegalovirus and schizophrenia
Cytomegalovirus is another example of an infectious
agent that has been linked to a specific psychiatric
disorder, schizophrenia. It is a b-herpesvirus initially
isolated in 1956 from children with congenital mental
retardation and hearing loss. CMV occurs worldwide
and is spread by personal contact, including saliva,
blood, urine, genital secretions and breast milk. It
thus spreads more quickly under conditions of poor
hygiene; in developed countries, approximately 60%
of adults are infected, while in developing countries,
the figure approaches 100%. Some observers have
said that CMV infections are more common in the
winter and spring,62 but others have not observed any
seasonal difference.
It is known that resistance to CMV infection is
associated with variations in the gene encoding tumor
necrosis factor-a;63 variations in this gene have also
been associated with an increased risk for schizophrenia in some studies64,65 but not others.66 Variations in the gene-encoding interleukin-10 have also
been associated with susceptibility to both CMV
infections and schizophrenia.67,68
The two most prevalent CMV clinical syndromes
are congenital infection and systemic infections in
immunosuppressed individuals. Congenital infections may produce mental retardation, hearing loss,
visual impairment and other deficits in the newborn.
In many cases, the infection is initially asymptomatic
but later decreases the child’s IQ.69 Once infected
with CMV, individuals remain latently infected for
life, although they may also become secondarily
infected with a different CMV strain.70 Suppression
of the immune system, as occurs in transplantation
and HIV infection, often leads to reactivation of CMV
infection with a range of clinical consequences,
including encephalitis, pneumonia, hepatitis, enteritis and retinitis.
In immune-competent individuals, most initial
CMV infections are asymptomatic. If symptomatic,
the most common syndrome is fever and enlarged
lymph nodes, and CMV is thought to be responsible
for approximately 10% of mononucleosis-like syndromes in young adults. Occasional cases of encephalitis have been reported. In one case, a 30-year-old
male developed chronic CMV encephalitis with
‘deficits in concentration, memory, manipulation of
knowledge, humor and emotional expression’.71 Similarly, a study of CMV antibodies in 323 individuals
with schizophrenia reported that those who had
primarily deficit symptoms (n = 88) were significantly
more likely to have CMV antibodies compared to
those who had nondeficit symptoms (n = 235;
P = 0.006).72 Another study of individuals with schizophrenia reported that ‘higher levels of CMV antibodies were associated with decreased performance
on baseline measures of verbal learning and memory.73 Also of interest is a case study of a young
woman who presented with auditory hallucinations,
delusions, tangential thinking and flattened affect and
was diagnosed with schizophrenia; while hospitalized, she died and was then diagnosed with CMV
encephalitis on the basis of retrospective antibody
titers and post-mortem findings.16
Neuropathologically, CMV is known to have an
affinity for the limbic system74 and to evoke a strong
glial response, producing cytokines and chemokines.75 It is unclear whether CMV’s effects on the
brain are primarily due to the direct effects of the virus
or are indirectly mediated by the immune response.
The histopathologic hallmark of CMV infections are
intranuclear inclusion bodies and scattered glial
nodules. Most neuropathological studies of CMV have
been done on immune-compromised individuals, and
it is unclear whether immune-competent individuals
exhibit similar findings. In animal studies, infecting
rats with a rat CMV shortly after birth was said to
produce ‘a deficit in sensorimotor gating upon
dopamine stimulation, supporting a possible link
between viral infection and schizophrenia’.76
Many studies have looked for evidence of CMV
infection in the blood, CSF and brain tissue of
individuals with schizophrenia. Fourteen serological
studies carried out prior to 1994, using less sensitive
assays and mostly patients with chronic schizophrenia, were negative (reviewed in Yolken and Torrey77).
More recently, five studies using more sensitive
assays and patients with a more recent onset of
schizophrenia have all reported a higher rate of CMV
seropositivity in the patients compared to controls
(reviewed in Torrey et al.78).
Of particular note was the study by Leweke et al.79
in Germany. They studied 36 first-episode, nevertreated individuals with schizophrenia; 10 individuals with schizophrenia who had been treated in the
past but were medication-free at the time of the study;
475
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Psychosis and microbial agents
RH Yolken and EF Torrey
476
2.5
***
2.0
*
*
1.5
1.0
CSF IgG antibody level
Serum IgG antibody level
2.0
1.5
**
Never therapy (n=36)
Past therapy (n=10)
Current therapy (n=39)
Controls (n=39)
1.0
0.5
0.5
0
0
Figure 2 Pathways of transmission of Toxoplasma gondii
from cats to humans.
39 individuals with schizophrenia with recent onset
but who were on medication at the time of the study
and 73 unaffected controls. As shown in Figure 2,
CMV immunoglobulin G antibody levels were significantly higher in both the serum (P < 0.001) and
cerebrospinal fluid (CSF) (P < 0.004) in individuals
with schizophrenia who had never been treated
compared to the unaffected controls. Noteworthy
was the stepwise gradient of antibody levels in both
serum and CSF from those who had never been
treated, those who had been treated in the past, those
who were presently being treated and the unaffected
controls, suggesting that antipsychotic medication
may have been decreasing the antibodies.
Other CMV studies of the CSF in individuals with
schizophrenia have been less conclusive. Since 1980,
eight studies have been done; four reported significantly increased CMV antibodies in the CSF of patients
compared to controls, while four others did not
(reviewed in Torrey et al.78). Nine studies have also
attempted to identify the CMV genome in post-mortem
brain tissue from individuals with schizophrenia, using
hybridization or PCR techniques. Eight of the studies
were unable to detect CMV in the brain tissue
(reviewed in Torrey et al.78); the other reported that ‘a
clear hybridization signal was detected with DNA from
the temporal cortex of a young man with the full
picture of schizophrenia’.80The Leweke et al. study,
cited above, suggests that treating individuals with
schizophrenia with antipsychotic drugs may reduce
antibodies to CMV, presumably by suppressing the
infection. This observation is consistent with studies
reporting that some antipsychotic drugs suppress the
replication of some infectious agents.81 Based on this
observation, two studies have also been carried out
using adjunct medications that suppress CMV replication in individuals with schizophrenia. In the first,
valacyclovir, a known antiviral drug, was used for a
16-week, double-blind trial for 65 outpatients with
schizophrenia. Among the 21 patients who were CMV
seropositive, there was ‘a significant improvement in
overall symptoms (P < 0.0005)’.82 No such improvement
Molecular Psychiatry
was noted for patients who were seropositive for other
herpes viruses.
In the other treatment study, 50 outpatients with an
acute exacerbation of schizophrenia were treated with
adjunctive celecoxib in a double-blind trial. Those
receiving the drug had a significant improvement in
their symptoms, especially between 2 and 4 weeks
(P = 0.001).83 Celecoxib is an inhibitor of cyclooxygenase (COX-2),84 and it is known that inhibition of
COX-2 blocks the replication of CMV.85 Based on the
results of these two treatment trials, additional tests
are underway.
Discussion
T. gondii and CMV are examples of infectious agents
that may be plausibly linked to schizophrenia. They
are a good fit epidemiologically, including a worldwide distribution and a peak exposure. They are
known to be neurotrophic and to alter human
behavior. They are capable of infecting individuals
in early life and are thus consistent with neurodevelopmental theories of schizophrenia. They are also
capable of reactivation in early adulthood, the peak
time for the onset of the symptoms of schizophrenia.
And they are known to be suppressed, to some degree,
by antipsychotic medications. They thus represent
examples of microbes that may have an etiological
relationship to a major psychiatric disorder.
There are two major limitations to any infectious
theory of schizophrenia: timing and causality: Since
most studies rely on the detection of infection in
individuals who already have schizophrenia, there
has been difficulty in distinguishing whether an
increased rate of exposure to an infectious agent is a
cause or an effect of the altered behavior that is
characteristic of schizophrenia. For example, it might
be argued that some of the concomitants of schizophrenia, such as hospitalization, homelessness and
the administration of medications, might alter the
host immune response and result in an increased
exposure to an infectious agent independent of the
factors that led to the initiation of the disease itself.
This problem is generic to all potential associations
between infection and chronic disease defined in
cross-sectional case control studies, since it can be
difficult to determine if the measured exposure
occurred before, during or after the initiation of the
disease process. The problem can be compounded by
the difficulty in identifying unaffected controls who
do not have the disease but who are likely to be
similar to the cases in terms of social and demographic factors that are related to exposures to
infectious agents.
The problem of timing has been partly addressed by
the evaluation of individuals with ‘recent onset’
schizophrenia who have not been previously hospitalized or, in some cases, have not received medications. Several studies in such populations have found
increased evidence of exposure to T. gondii as well as
to other infectious agents. These studies, however,
Psychosis and microbial agents
RH Yolken and EF Torrey
might also be affected by exposures occurring around
the time of disease onset, particularly in individuals
with prolonged periods of undiagnosed and untreated
psychosis.
For this reason, there has been an increased
recognition of the importance of prospective cohort
studies for the evaluation of the risk of environmental
exposure in complex disorders. Such cohorts have
proven to be invaluable in addressing the long-term
effects of diet, smoking and other toxic exposures on
chronic diseases such as heart disease, stroke and
cancer. Of particular importance in terms of the study
of the role of infectious agents in schizophrenia are
cohorts in which blood samples have been obtained
and stored, since such samples can be retrieved after
the diagnosis of the disease and used to assess predisease exposure to infectious agents by the measurement of specific antibodies.
One type of cohort study that has been employed to
examine the role of exposures in the subsequent
development of schizophrenia has involved the study
of pregnant women and their offspring. These have
either been cohorts specifically set up for the study of
diseases or population-based cohorts that have made
use of neonatal blood samples obtained for the
analysis of neonatal metabolic diseases and then
stored for future studies. In two prospective neonatal
cohorts, it was found that perinatal exposure to
T. gondii resulted in an increased risk of schizophrenia in later life. Additional perinatal exposures that
have been found to be associated with increased risk
of subsequent schizophrenia in cohort studies
include rubella virus, influenza viruses, enteroviruses
and HSV-2 in some populations but not others.
Increased risk of schizophrenia has also been associated with nonspecific markers of inflammation such
as cytokines and with other inflammatory conditions
such as pre-eclampsia.
Perinatal cohort studies have been important in
identifying exposures in the prenatal period associated with risk of schizophrenia in later life.
However, these studies cannot evaluate exposures
beyond the neonatal period. Similarly, cohorts of
older adults, such as the Framingham or Cache
County studies, are directed largely at the study of
diseases that occur in later life and enroll the majority
of their subjects after the age of risk of schizophrenia.
Fortunately, there are cohorts of young adults that can
be employed to study diseases such as schizophrenia
with onset in young adulthood. The most widely
employed to date has been the cohort of individuals
in the US Military maintained by the Army Medical
Surveillance Activity. This cohort has been employed
to study the role of Epstein–Barr infection in multiple
sclerosis as well as other associations with infectious
diseases. Recently, researchers have identified individuals who developed schizophrenia while they
were in the military and measured antibodies contained in archived blood samples obtained both
before and after the onset of their symptoms. As
noted previously, preliminary analysis of these
samples documented an increased level of antibodies
to T. gondii in samples obtained approximately
2 years prior to the diagnosis of schizophrenia. This
study, combined with the perinatal studies and the
studies of recent-onset individuals cited above,
strongly suggests that a substantial part of the
exposure to Toxoplasma in individuals with schizophrenia occurs prior to the onset of schizophrenia and
is not solely a result of post hoc exposures. Such
studies provide the framework for attempts to prevent
schizophrenia through the prevention of Toxoplasma
infection or the treatment of infected individuals.
The other major limitation is related to the
difficulty of proving causality. The interactions
between infectious agents and host factors resulting
in complex disorders such as schizophrenia generally
do not follow the rules laid down by Robert Koch and
his co-workers at the end of the nineteenth century.
These rules, generally known as Koch’s postulates,
require that there be a one-to-one correspondence
between an infectious agent and a disease process.
It is clear, however, that the relationship between
infectious agents and chronic diseases often does not
follow the straightforward associations defined by
Koch’s postulates but rather follows a more complicated course comprising multiple pathways leading
to diverse clinical outcomes. These pathways can
involve more than one infectious agent resulting in
the same disease, as well as many individuals who
are infected but who do not develop the target disease
in their lifetime. This latter phenomenon is based on a
number of factors, including the timing of infection,
the nature of the infecting strain and the genetic
makeup of the host.
Guidelines for evaluating the relationship between
an infectious agent and a chronic disorder to supplant
Koch’s postulates have been devised by a number of
authors. The most widely cited are those devised by
British statistician Austin Bradford Hill published in
1985, which identify quantitative degrees of association between exposure and disease and incorporate
biological plausibility and coherence into the criteria.86
The extent to which the association between Toxoplasma infection and schizophrenia fulfill the Hill
criteria has been the subject of a recent review.87
Specifically, with regard to T. gondii, the association
between Toxoplasma infection and schizophrenia
fulfills many of the criteria, including strength,
consistency, temporality, plausibility and analogy.
The main factor that is missing is direct evidence that
the replication of Toxoplasma organisms is associated
with ongoing symptoms of schizophrenia. The most
straightforward way to test this hypothesis would be
to demonstrate that the inhibition of Toxoplasma
replication by pharmacological means would result in
a decrease in the symptoms of schizophrenia and an
alteration in the clinical course of the disease. In the
past, this approach has not been feasible because of
the lack of a safe and effective method for the
treatment of Toxoplasma that would be suitable for
administration to individuals with schizophrenia.
477
Molecular Psychiatry
Psychosis and microbial agents
RH Yolken and EF Torrey
478
Recently, however, it has been shown that derivatives
of artemisinin, which has proven to be safe and
effective for the treatment of malaria, also inhibit the
replication of Toxoplasma, which shares a substantial
portion of its genome with malaria organisms.88
A number of clinical trials examining the efficacy of
artemisinin derivatives in individuals with schizophrenia are in progress. Their successful conclusion
would provide the most direct evidence for a role of
Toxoplasma in the etiology of schizophrenia and
would open a new era in methods for the diagnosis,
prevention and treatment of this devastating illness.
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