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2009

Infectious Findings for Schizophrenia

December 16, 2009
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Robert Yolken, M.D.

Could childhood exposure to a common microbe, passed along through feline waste, raise the risk for schizophrenia? Pediatric infectious disease specialist Bob Yolken and colleagues are building a case.

When Bob Yolken was a student at Harvard Medical School, he never once heard the term schizophrenia. 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, while Yolken was more interested in the specialties of infectious disease and pediatrics. And if someone had suggested that infections had anything to do with schizophrenia, says Yolken, “the idea would have seemed pretty far-out.”

Today, however, Yolken, director of Developmental Neurovirology at Hopkins, 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 he hopes will lead to better drugs for patients plagued by the disease. The shift in Yolken’s career direction began with a phone call.

It came around 1980, soon after Yolken had arrived at Hopkins, from a psychiatrist named E. Fuller Torrey at St. Elizabeths Hospital, in Washington, D.C. Torrey was intrigued by the idea that a microbe of some sort might cause schizophrenia. Several lines of evidence led him to this conclusion, including long-forgotten reports published in the late 1800s describing patients who 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.

But not Yolken. By the time Torrey called, Yolken had completed his medical training at Harvard, an internship and residency in pediatrics at Yale, and was at the National Institutes of Health. His studies at NIH focused on a variety of infectious diseases, particularly those causing severe diarrhea in children, and in time Yolken would establish an international reputation in this field. But his expertise then did not include infections of the nervous system, not to mention those that might contribute to mental illness. However, Yolken listened intently while Torrey explained his hypothesis. When Torrey was through, he told him, “It sounds like an interesting idea.”

Looking back, Yolken now says two factors made him receptive to Torrey’s hypothesis. One was the notion that infections early in life could lead to chronic diseases in adulthood. Some of his colleagues, for instance, were studying the possible link between a bacterial or viral infection and inflammatory bowel disease. So it was not inconceivable that an infection of some sort could contribute to schizophrenia.

Another influence was Yolken’s wife, Faith Dickerson, a psychologist, who worked closely with patients with schizophrenia. He learned from her that available medications could alleviate the hallucinations, delusions, and other symptoms of schizophrenia for some patients, but he also learned that in other patients, symptoms persisted despite medication. “Bob was aware of the intractable nature of many patients’ disorders,” says Dickerson, “and how they struggled.”

So Yolken accepted Torrey’s offer to collaborate. One study led to another, and then, over the next 30 years, to many others—as well as to a close friendship. In examining the connection between schizophrenia and a host of different microbes, their studies implicated several infectious agents in the disease. Mounting evidence, for example, indicates that people whose mothers were exposed to influenza while they were in the womb triple their risk of schizophrenia. Other studies suggest that early exposure to the herpes simplex virus type 2 or cytomegalovirus also raise the risk.

One microorganism, however, now especially attracts YolkenToxoplasma gondii, which can reside in many different warm-blooded animals—rats, mice, cows, cats, and people. The parasite requires a feline host to complete its life cycle and form 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. Pregnant women are cautioned to not clean litter boxes because T. gondii can infect the unborn child, causing 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, but the immune system usually keeps the parasite from causing illness.

“Toxoplasma is remarkable it 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, pointing to dozens of studies that now support a connection. Among these are studies that compare the level of Toxoplasma antibodies in people who have schizophrenia and those who don’t. Yolken and Torrey recently analyzed all of the scientific evidence on this relationship – some 23 studies in all – which showed that patients with schizophrenia were almost three times as likely as those without to test positive for T. gondii antibodies (Schizophrenia Bulletin 2007).

In addition, researchers have found higher levels of Toxoplasma antibodies in newborn infants who later develop schizophrenia and in pregnant women whose babies go on to develop the disorder. Finally, in a recent study conducted with researchers from the Walter Reed Army Institute of Research, Yolken examined antibody levels in blood samples drawn from 712 recruits, a group that included 180 recruits who eventually received a diagnosis of schizophrenia. The results, which the researchers reported in the January 2008 American Journal of Psychiatry, showed that personnel who had been infected with Toxoplasma had a 24 percent greater risk of developing schizophrenia.

T. gondii infections that occur during critical times in brain development may predispose a person toward schizophrenia or compound an already present risk, says Yolken. In that sense, the early psychiatrists who intuited that childhood lay the groundwork for schizophrenia had one thing right—the disorder does appear to have its roots in childhood or even earlier. While early psychoanalysts ascribed blame to the “schizophrenogenic mother,” modern-day scientists point to genes and environmental factors such as T. gondii.

Yolken and Torrey 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 constellation 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. A subsequent infection may reactivate the parasite. The hormonal shifts and remolding of the brain that occur during adolescence may play a role, a theory that would help explain why most cases of schizophrenia appear in the late teens and early 20s.

Pediatricians should be aware of the Toxoplasma research and its implications, says Yolken. Pregnant women should always take precautions when emptying cat litter boxes, he says, and they and their children should avoid eating raw or undercooked meat, especially pork, lamb and venison.

While prevention is important, Yolken is also hoping that his research might yield new treatments for T. gondii infections. His ultimate hope is that such treatments might also cure schizophrenia, or at least reduce its symptoms. The drug that appears most promising is a compound now used to treat malaria 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 demonstrated that artemisinin could kill T. gondii. To Yolken, the implications were obvious: The anti-malarial 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 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 the January 2009 Journal of Antimicrobial Chemotherapy.

Yolken and Dickerson are also beginning a clinical trial of an artemisinin compound. During the eight-week trial, patients with schizophrenia 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 also treat the incurable disease that is schizophrenia and make people better.”