OT:Infectious Agents N Schizophrenia/Bipolar Disorder/viruses/Toxoplasma/herpes/

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Infectious Agents in Schizophrenia and Bipolar Disorder

By H. Yolken, MD and E. Fuller Torrey, MD

Page 1 of 2

edited by Stanley N. Caroff, MD

June 2006, Vol. XXIII, No. 7

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-compulsivNew researc

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, ?-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 colleagues4 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-An additional important reason

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.T g

Since 1956, more than 20 studies have compared antibodies to T gondii in

adults with and without schizophrenia.Since 1956, more than 20 studies have

compared antibodies to T gondii in adults with and without

schizophrenia.<WBR>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 OthSince 1956, more than 20 studies have compared antibodies to T gondii

in adults with and without schizophrenia.<WBR>10 An overall analysis of the

studies indicates that serologic ev

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.Li

Comparison studies of persons with and without schizophrenia or bipolar

disorder show that HSV-1 infection significantly increases cognitive

dysfunction-Comparison studies of persons with and without schizophrenia or

bipolar

disorder show tComparison studies of persons with and without schizophrenia or

bipolar disorder show that HSV-1 infection significantly increases cognitive

dysfunction-<WBR>especially recent memory defi

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.

Page 2: Cytomegalovirus ...to be continued...

Part 2

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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.Endog

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 s 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.

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