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Infectious Agents in Schizophrenia and

Bipolar Disorder
Psychiatric Times. Vol. 23 No. 7; http://www.psychiatrictimes.com/home
By Robert H. Yolken, MD and E. Fuller Torrey, MD | June 1, 2006

The idea that schizophrenia and bipolar disorder might be caused by infection is not new. This
was a prominent hypothesis in the early years of the last century. For example, an article
entitled, “Is insanity due to a microbe?” was published in Scientific American as early as 1896.
Research to test this hypothesis by identifying causative viruses was already being conducted
by the 1930s, when data were reported from experiments in which cerebrospinal fluid (CSF)
from patients with schizophrenia was injected into rabbit brains. 1

New research in the field continues, aided increasingly by impressive technologic advances in
microbiology and virology. As recently as the past decade, reports documented the presence of
influenza virus, rubella virus, bovine disease virus, and other infectious agents in patients with
schizophrenia and bipolar disorder, as well as the presence of other infectious agents in
childhood pediatric autoimmune neuropsychiatric disorder associated with streptococcal
infections (PANDAS) and obsessive-compulsive disorder.

In this article, we briefly highlight the background of such research; discuss our own research on
Toxoplasma gondii, herpes simplex virus (HSV), Cytomegalovirus (CMV), and endogenous
retroviruses; and consider the future implications of such research for psychiatric clinicians.

Background and rationale

Why should we look for infectious agents in schizophrenia and bipolar disorder? Such a
hypothesis is consistent with the known genetic contributions to these disorders. Indeed, a
genetic predisposition is well established for most chronic infectious diseases, including
tuberculosis, malaria, polio, AIDS, and peptic ulcers caused by Helicobacter pylori.2 The
hypothesis is consistent with the role of neurotransmitter abnormalities in schizophrenia and
bipolar disorder, because specific infectious agents have been shown to alter dopamine,
serotonin, glutamate, γ-aminobutyric acid, and acetylcholine in animal models. The hypothesis
is also consistent with neurodevelopmental models of schizophrenia and bipolar disorder.
Pearce3 and others developed animal models that show how exposure to specific infectious
agents during neurodevelopment correlates with later behavioral alterations in animals.

An additional important reason to look for infectious agents in schizophrenia and bipolar
disorder is that CNS infection by specific pathogens frequently mimics the clinical symptoms of
primary psychiatric diseases. For example, Caroff and colleagues 4 reviewed 108 cases of
psychiatric disorders resulting from suspected or confirmed CNS viral infections; in 62 cases, a
specific virus was implicated, including HIV, HSV-1, HSV-2, Epstein-Barr, and CMV; and
measles, mumps, coxsackie, and influenza viruses. Among bacteria, the fact that the spirochete
of syphilis can cause the symptoms of schizophrenia was well known to psychiatric clinicians of
an earlier era. More recently, infection with the spirochetal organism Borrelia burgdorferi has
also been associated with schizophrenia-like symptoms in some persons.5
Another reason to look for infectious agents in schizophrenia and bipolar disorder is the well-
established association between the risk of these disorders and winter-spring seasonal birth.6
There have been more than 200 studies of this phenomenon, and it remains one of the most
highly replicated findings of these diseases. Because many infectious diseases occur
seasonally, with a peak in the winter or spring, it is reasonable to postulate that fetal or newborn
infection could contribute to subsequent mental illness. 7

Current research

At the present time, we are focusing our research on 4 infectious agents as possible causes of
schizophrenia and bipolar disorder. These are T gondii, HSV-1 and HSV-2, CMV, and
endogenous retroviruses.

Toxoplasma gondii

T gondii is a protozoan parasite whose definitive host is the cat family. Humans become
infected by ingesting oocysts shed in the feces of infected cats or by eating undercooked meat
from an animal that came into contact with infected cat feces. T gondii is one of the most
widespread human parasites; 10% to 20% of Americans test seropositive by adulthood.
Exposure to T gondii during early pregnancy can cause severe fetal CNS abnormalities.
Exposure during late pregnancy was never considered a problem until recently, when animal
data showed that late exposure to the organism causes behavioral changes, neurologic
symptoms, and stillbirths.8,9

Since 1956, more than 20 studies have compared antibodies to T gondii in adults with and
without schizophrenia.10 An overall analysis of the studies indicates that serologic evidence of
Toxoplasma infection is almost 3 times more common in persons with schizophrenia than in
controls living in the same geographic region.Two additional studies reported an increased level
of T gondii antibodies in the late-pregnancy serum of women giving birth to infants in whom
schizophrenia later developed. 11,12 Other studies have reported greater childhood exposure to
cats among persons with schizophrenia than among controls. 13,14 Our research is focusing on
the timing of Toxoplasma infections in relation to development, as well as on possible
differences in T gondii strains and human genetic susceptibility.

Herpes simplex viruses

Like Toxoplasma, HSV-1 and HSV-2 are common causes of infection in humans. HSV-1 may
be spread by either sexual or nonsexual contact with infected persons, while HSV-2 is primarily
spread through sexual contact. Both of these viruses are known to cause encephalitis and to be
highly neurotropic. Traditionally, however, these viruses have been regarded as relatively
benign in the majority of asymptomatic patients who carry them. Recent data suggest that this
may not be true. One study evaluated the mothers of patients in whom schizophrenia or bipolar
disorder developed. These women had increased levels of HSV-2 serum antibodies just before
parturition.15

Comparison studies of persons with and without schizophrenia or bipolar disorder show that
HSV-1 infection significantly increases cognitive dysfunction—especially recent memory
deficits—in persons with schizophrenia or bipolar disorder. 16,17 This did not occur in persons
infected with other viruses in the herpes family and also did not occur in persons without
schizophrenia or bipolar disorder who were infected with HSV-1.
In a follow-up study, Dickerson and associates18 showed that a polymorphism on the COMT
gene (COMT Val 158 Met polymorphism) also increases cognitive dysfunction; this suggests a
synergistic effect between HSV infection and the gene. This kind of interaction may be a model
for future research that integrates multiple factors in the development of schizophrenia and
bipolar disorder.

Cytomegalovirus

CMV is another member of the herpes family of viruses. Infection is widespread and is known to
occasionally cause encephalitis, primarily in patients with immunosuppression.

In contrast to older studies, recent studies report significantly more CMV antibodies in persons
with schizophrenia than in controls. In a study by Leweke and colleagues, 19 for example, 36
treatment-naive schizophrenic patients had significantly more antibodies in their sera (P < .001)
and CSF (P < .003) than did 73 controls. This confirms earlier CSF findings published by our
group.20 Another recent study reports that serum antibodies to CMV are particularly high in
schizophrenic persons who have predominantly negative symptoms (the so-called deficit
syndrome).21

Finally, a recent treatment trial showed significant symptomatic improvement in schizophrenic


patients who were treated with valacyclovir, an antiviral agent effective against herpes viruses. 22

Endogenous retroviruses

Endogenous retroviruses are DNA elements that have become part of the human genome
through infection and integration into germ line cells of humans and nonhuman primate
progenitors. Retroviruses lie dormant most of the time. When activated, however, they can
influence the transcription of genes above or below the site of their chromosomal integration.
Genetic polymorphisms of endogenous retroviruses have been linked with an alteration in
immune response and increased susceptibility to autoimmune disorders.23

Endogenous retroviruses share properties of both genes and infectious agents, and are thus
potential links between the two. 24 Of particular interest is the fact that endogenous retroviruses
may be activated by infections with herpesviruses or protozoan organisms such as Toxoplasma,
providing a potential link between infectious agents and genetic elements as causative factors in
human psychiatric diseases. Increased retroviral transcription in the CSF and blood of persons
with recentonset psychosis supports a possible role for human endogenous retrovirus in the
development of schizophrenia. 25,26

Implications for clinicians

Proving a causative role for infectious agents in schizophrenia and bipolar disorder would open
the door to new treatments and disease prevention strategies. With the support of The Stanley
Medical Research Institute, we are conducting several double-blind treatment trials that involve
the use of adjunctive antibiotics and antiviral medications in persons with schizophrenia and
bipolar illness. To date, these medications show some promise in patients with recent-onset
disease. The results are less remarkable in persons with long-standing illness. In the future, it
might even be possible to develop a vaccine to protect children against possible infections that
contribute to these 2 mental illnesses.
Even with what is known today, in clinical settings, some patients who present initially with
symptoms suggestive of schizophrenia or bipolar disorder could instead be in the initial stages
of viral encephalitis. Some physicians would argue that patients with first-admission psychosis
should have a lumbar puncture and CSF analysis, adding other studies as appropriate if
indicated by an increase in CSF protein or lymphocytes. A small sample of the CSF could be
frozen and stored for future analysis. With further advances in research at the interface between
psychiatry and infectious disease, these samples may eventually provide the key to proving the
connection between infection and mental disturbance, and pave the way for pharmacologic
treatment specifically targeted to that causative infectious organism.

Dr Yolken is director of the Stanley Division of Developmental Neurovirology and professor,


department of pediatrics, The Johns Hopkins University School of Medicine, Baltimore. Dr
Torrey is associate director for laboratory research, The Stanley Medical Research Institute, and
professor of psychiatry, Uniformed Services University of the Health Sciences, Bethesda, Md.