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an online version of the magazine Fall 2009
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Infectious Enthusiasm  
 
  Could a common microbe, passed along through feline waste, raise the risk for schizophrenia? Neurovirologist Bob Yolken and colleagues are building the case.

By Melissa Hendricks
 
 
 
 

When Bob Yolken was a student at Harvard Medical School, he never once heard the term schizophrenia.


Yolken
 

Not in a lecture. Not in a clinical rotation. It simply wasn’t part of the standard curriculum at Harvard back in the late 1960s and early 1970s. The omission did not bother Yolken at the time. Schizophrenia was the domain of psychiatrists, many of whom still attributed the illness to bad mothering. Yolken was more interested in virology; and if someone at the time had suggested that a virus or other microbe had anything to do with schizophrenia, says Yolken, “the idea would have seemed pretty far-out.”

Today, however, Yolken the virologist spends a good portion of his research time studying a parasite called Toxoplasma gondii, which he is “strongly convinced” contributes to schizophrenia. Yolken’s work culminates three decades of research in pursuit of infectious agents that may be connected to the disabling brain disorder—and which Yolken hopes will lead to better drugs for patients who are plagued by the disease (roughly 1 percent of the adult U.S. population).

The shift in Yolken’s career direction began with a phone call.

It came around 1980 from a psychiatrist named E. Fuller Torrey at St. Elizabeth’s Hospital, in Washington, D.C. Torrey had become intrigued by theory that challenged conventional notions of schizophrenia. The new idea was that a microbe of some sort might cause the disease. Several lines of evidence had led him to this conclusion, including long-forgotten reports published in the late 1800s describing patients who had experienced psychoses during the course of an infectious illness. Torrey tried discussing his idea with other scientists, to no avail. “People thought it was an absurd idea,” he recalls.

Then a colleague suggested that Torrey contact Yolken, who by then had earned an international reputation as a specialist in viruses that cause severe diarrhea in children. Yolken had no experience in neurovirology. However, he had begun reading an emerging literature suggesting that some infectious agents might not only cause acute infections; they might also contribute to certain chronic diseases.

Yolken listened patiently on the phone while Torrey elaborated his thesis. When Torrey had finished, Yolken told him, “It sounds like an interesting idea.”

Their conversation led to a research study and then, over the next 30 years, to many others—as well as to a close friendship. (The pair plot their research plans at sporting events—baseball, lacrosse, hockey.) The two scientists have examined the connection between schizophrenia and a host of different microbes, including cytomegalovirus, herpes simplex virus, and influenza. While several of those studies have presented intriguing leads, says Yolken, the most substantial evidence implicates Toxoplasma, which is where he now focuses most of his research energy.

T. gondii can reside in many different warm-blooded animals—rats, mice, cows, cats, people. But it requires a feline host to complete its life cycle. It forms oocysts, or spores, in the cat’s intestines that are shed in the cat’s feces. A person can contract an infection by emptying a litter box, or ingesting meat or water contaminated with the parasite. If a pregnant woman passes T. gondii to her unborn child, the infection, or toxoplasmosis, may cause mental retardation, hearing loss, or other problems.

Most cases of toxoplasmosis go unnoticed or cause only mild symptoms easily mistaken for a cold or flu. In fact, about one-third of all people worldwide have probably contracted T. gondii infection. “Toxoplasma is remarkable in its ability to infect humans,” says Yolken. “I probably have Toxoplasma organisms in my brain.”

It is these latent infections that Yolken and Torrey believe may raise the risk of schizophrenia.

The scientists are cautious here. First, they say, Toxoplasma appears to be involved in some, but far from all, cases of schizophrenia. Second, Toxoplasma alone does not appear sufficient to cause the disease. Most likely, a number of factors are required—genes, various environmental triggers—and the combination may not be the same in every person.

But in cases where T. gondii does play a role, the researchers propose, the initial infection probably occurs early in life—in the womb or during early childhood. Then, later in life, a second “hit” may reactivate the parasite; this resurgence then may help bring about schizophrenia, perhaps especially in people with a genetic predisposition to the disease. Yolken cannot say precisely what the second “hit” may be. One possibility is that the hormonal shifts of adolescence play a role, a theory that would help explain why most cases of schizophrenia appear in the late teens and early 20s.

Dozens of studies now support the theory connecting T. gondii to schizophrenia. Many of these are antibody studies, which compare, for example, the level of Toxoplasma antibodies in blood drawn from people who have schizophrenia and those who don’t. Yolken and Torrey recently performed a meta-analysis of all the scientifically rigorous studies on T. gondii antibodies in schizophrenia. Their results, which involved 23 studies in all, showed that patients with schizophrenia were almost three times as likely as those without to test positive for T. gondii antibodies. The study appeared in the 2007 Schizophrenia Bulletin.

Another area of investigation has begun to reveal the mechanisms T. gondii might use when infecting the brain, and how they might help give rise to schizophrenia. One clue, says Yolken, comes from studies by scientists in Britain showing that T. gondii has genes that are critical for the production of dopamine. Numerous studies have tied excess dopamine to schizophrenia, but scientists have struggled to explain the source of the irregularity. Now, at least in some patients, T. gondii may offer the answer.

But Yolken is not content to stop there. While existing research shows correlation, definitive proof can only come by demonstrating causation. Toward that end, Yolken is now attempting to show that a drug that inhibits T. gondii can cure schizophrenia, or at least reduce its symptoms.

The drug that appears most promising is a compound called artemisinin, an extract of the weed Artemesia annua, or sweet wormwood, which grows wild in China. Yolken learned about the compound on a trip to China in 2005 where he met scientists who had demonstrated that artemisinin could kill T. gondii. To Yolken, the implications were obvious: The drug might be a treatment for schizophrenia.

Back at Hopkins, Yolken launched a project aimed at designing new derivatives of artemisinin and testing the compounds’ ability to target T. gondii. He asked virologist Lorraine Brando to lead the studies.

The trick to the research is finding an artemisinin derivative that inhibits T. gondii but does not harm neurons. Several derivatives appear to fulfill these requirements, says Yolken, findings that he and Brando and their colleagues reported in a recent issue of the Journal of Antimicrobial Chemotherapy. They are now planning animal studies.

Yolken is also beginning a clinical trial of an artemisinin compound not yet gained FDA approval. During the eight-week trial, schizophrenia patients will take daily artemisinin pills, while the researchers test their blood for levels of T. gondii antibodies and monitor their symptoms. “Our hope,” says Yolken, “is to identify infections like toxoplasmosis, and by treating those infections to take the incurable disease that is schizophrenia and make people better.”

Such an accomplishment, he says, is not without precedent. Doctors used to believe that stress alone caused peptic ulcers—until Australian physician Barry Marshall proposed that the condition arose from a bacterium, a claim he proved by swallowing a cup of the bacteria and then curing himself of the ensuing ulcer with an antibiotic. “No one,” says Yolken, “thought it would work.” *

 

 
 
 
 
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