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Clinical and Research News
New Findings Boost Theory That Infection Causes Schizophrenia
Psychiatric News
Volume 45 Number 6 page 1-19

Call it an instance of science being stranger than science fiction, and of nature's unintended consequences.

In 2000, a team of British researchers published a remarkable paper in the journal of the Royal Society titled "Fatal Attraction in Rats Affected With Toxoplasma Gondii." It seems that rodents infected with Toxoplasmosis gondi (T. gondii), a parasite that normally thrives in cats, become fatally attracted to cat urine, causing them to shed their normal avoidant behavior in the presence of a cat.

Naturally, cat catches rodent and devours it, with the result that the parasite T. gondii is again where it belongs: in a feline host.

Observing this case of attraction gone fatally wrong, the researchers, from the University of Oxford, postulated that T. gondii, one of nature's most successful organisms, had developed an ingenious evolutionary mechanism for manipulating the behavior of the rodent—in whom the parasite would have reached a dead end—so that the rodent seeks out, suicidally, the feline host in which the parasite can thrive and complete its life cycle.

Fast forward to 2009 when another group of researchers seeking to explore the neurochemical mechanisms for the parasite's behavioral manipulation of its host discover a likely culprit. In a paper published in the March 2009 PLoS One, Glenn McConkey, Ph.D., and colleagues at the University of Leeds found that the genome of the T. gondii parasite encodes the enzyme tyrosine hydroxylase, the central enzyme in dopamine synthesis.

"Intriguingly, dopamine is the most logical neurotransmitter candidate for altering the avoidant behavior of the rodent," McConkey told Psychiatric News. "So it would make sense for the parasite to increase dopamine. For the parasite, this is an ideal way to manipulate the behavior of the host."

(PLoS One, published by the Public Library of Science, is an international peer-reviewed, open-access publication posted at <www.plosone.org>.)

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And this strange cat-and-mouse story has yet another wrinkle.

For decades, an excess of dopamine has been implicated in schizophrenia. And so last year's discovery that T. gondii synthesizes dopamine has lent new credence to an intriguing, though not universally accepted, theory—that at least some forms of schizophrenia may be caused by infection.

Among researchers inclined to the theory, T. gondii has been one, among several, of the most prominent candidates.

"Humans infected with T. gondii will form the same cysts on the brain as are found in infected rodents when high levels of the gene involved in dopamine synthesis are expressed," McConkey said. "While production of dopamine in the rodents could be an evolutionary mechanism devised by the parasite, in humans it would be merely accidental. But now suddenly, this provides a possible link to the observed correlation of T. gondii with some forms of schizophrenia."

The theory of an infectious etiology for at least some forms of schizophrenia has a long history, though it is still outside the mainstream. As far back as the 1960s, British epidemiologist Edward Hare, Ph.D., documented a marked increase in late-winter and early-spring births of people with schizophrenia, a finding that pointed to an infection, possibly acquired during winter months in utero.

Psychiatrist E. Fuller Torrey, M.D., a long-time proponent of the theory, published a paper in the Lancet as early as July 1973 titled "Slow and Latent Viruses in Schizophrenia."

Since then, Torrey has published a number of papers with Johns Hopkins University pediatrician and virologist Robert Yolken, M.D., showing increased antibodies to T. gondii—possibly acquired in utero or early childhood through exposure to cat feces, undercooked meat, or contaminated water, dirt, or sand—among people with schizophrenia.

Meanwhile, infectious agents have been implicated in other diseases—the heliobacter pylori virus in peptic ulcers, the papilloma virus in cervical cancer—that had been considered unlikely candidates for infection. "It's no longer a theory from Mars," Torrey told Psychiatric News. "We've arrived on planet Earth."

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Now, a report published online in AJP in Advance on February 1 by Alan Brown, M.D., of Columbia University and colleagues, reviews more than 40 studies looking at seroepidemiologic findings, ecologic data, and maternal reports on prenatal exposure to influenza and other infectious agents and the development of schizophrenia.

They found that odds ratios for associations between schizophrenia in offspring and serologically documented maternal influenza, elevated levels of antibody to T. gondii, and other peri-conceptional genital or reproductive infections ranged between 3.0 and 5.0.

The study, "Prenatal Infection and Schizophrenia: A Review of Epidemiologic and Translational Studies," was done in collaboration with Catherine Schaefer, Ph.D., director of the Kaiser Permanente Research Program on Genes, Environment, and Health, and Barbara Cohn, Ph.D., director of the Child Health and Development Studies, funded primarily by the National Institutes of Health.

In a study published in the April 2005 American Journal of Psychiatry, titled "Maternal Exposure to Toxoplasmosis and Risk of Schizophrenia in Adult Offspring," Brown and colleagues conducted serological assays for Toxoplasma antibody on maternal serum specimens from pregnancies giving rise to 63 cases of schizophrenia and other schizophrenia spectrum disorders and compared them with assays from 123 matched healthy subjects.

They found that the adjusted odds ratio of schizophrenia/schizophrenia spectrum disorders for subjects with high maternal Toxoplasma IgG antibody titers was 2.61.

"The infectious theory has garnered more interest in the research community," Brown told Psychiatric News. "This is being driven in part by accumulating data from epidemiological studies of schizophrenia and translational neuroscience in which offspring exposed prenatally to immune challenge and infection show evidence of neurobiological abnormalities found in schizophrenia."

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Still, the pathogenic theory of schizophrenia runs counter to years of orthodox thinking that schizophrenia is a congenital, organic brain disorder. Maternal and intrauterine infections are notably common, so one question is that if schizophrenia is infectious in origin, why aren't more offspring born with schizophrenia?

But proponents acknowledge that infection alone is unlikely to cause schizophrenia. "Infections are almost certainly interacting with susceptibility genes and other environmental factors," Brown explained. "So gene-environment interactions likely play a very important role."

Nor do proponents of the pathogenic theory insist that infection is necessarily the cause of all schizophrenia.

"While replication in independent samples is warranted, the data from our sample suggest that up to approximately 30 percent of schizophrenia cases could be prevented in the offspring of the pregnant population [in the review appearing in AJP in Advance] if we were to completely eliminate three of the infections we studied—influenza, elevated Toxoplasma antibody, and peri-conceptional genital-reproductive infections," Brown told Psychiatric News.

While complete eradication is highly unlikely, Brown says, the finding has implications for prevention and treatment (see Can Infection-Related Schizophrenia Be Prevented?).

More "orthodox" researchers acknowledge that infection may be a factor in a more expansive research vision looking at "domains of psychosis" in which schizophrenia-like symptoms stem from different gene-environment interactions.

"Most people acknowledge today that schizophrenia is never going to be found to have a single etiology," said psychiatric researcher and AJP deputy editor Carol Tamminga, M.D., of the University of Texas Southwestern Medical Center. "It's more likely a syndrome like congestive heart failure than a disease like Parkinson's with a single molecular lesion. So we can assume that schizophrenia is a diagnosis with multiple etiologies and overlapping risk factors.

"We know genetics and environmental factors are risks," she continued. "Keeping an open mind, I think we will find a list of risk genes and a list of environmental factors, and we will have to see how both of those play out in producing symptoms of a brain disease like schizophrenia."

An abstract of "Fatal Attraction in Rats Infected With Toxoplasma Gondii" is posted at <www.ncbi.nlm.nih.gov/pubmed/11007336>. "A Unique Dual Activity Amino Acid Hydroxylase in Toxoplasma Gondii" is posted at <www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0004801>. "Prenatal Infection and Schizophrenia: A Review of Epidemiologic and Translational Studies" is posted at <http://ajp.psychiatryonline.org/cgi/reprint/appi.ajp.2009.09030361v1>. "Maternal Exposure to Toxoplasmosis and Risk of Schizophrenia in Adult Offspring" is posted at <http://ajp.psychiatryonline.org/cgi/content/full/162/4/767>.blacksquare

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