Medical Breakthrough: The Viral Link to Mental Illness

Flu, AIDS, meningitis, Ebola, polio, herpes, measles, rabies—the list of diseases caused by viruses is a litany of woe ranging from the merely annoying to the deadly. Every year almost two million people are killed by the human immunodeficiency virus (HIV), and around half that many people succumb to viral hepatitis infections. The economic toll of viral illnesses is nearly as staggering as the human one; flu costs the United States an estimated $25 billion a year, and HIV costs $36 billion. To make matters worse, new viruses continue to appear (see “Virus Hunter” below), often after hiding in animal populations for centuries before moving into humans—as did HIV, avian flu, and severe acute respiratory syndrome (SARS). But while public health officials and physicians focus on the threat of emerging viruses, little-noticed research is implicating these primitive microbes in diseases long thought to have nothing to do with them: mental illnesses.

The notion that “insanity is infectious,” as virologist Ian Lipkin of Columbia University’s Mailman School of Public Health bluntly puts it, goes back to antiquity. As late as the 1800s, the mentally ill were locked away because, among other reasons, they were thought to be contagious. The notion wasn’t completely misguided. Until the discovery of penicillin ushered in the age of antibiotics, a major cause of mental illness was syphilis. But biomedicine is subject to fads and fashion no less than skirts are, and over the last 40 years disease detectives seeking the cause of mental conditions such as schizophrenia, bipolar disorder, autism, and obsessive-compulsive disorder have turned from microbes to genes as the cause. And now, a parade of discoveries suggests that viruses may be the culprit rather than your family tree. The new research indicates that viral infection can affect the developing brain and contribute to mental illnesses even before birth.

At first the evidence for a viral link to mental illness was spotty and inconsistent. Early studies piggy-backed on observations that when mothers suffered an infection during pregnancy, the children who were in utero at the time had an elevated risk of developing schizophrenia. But rigorous studies of whether that link was real produced contradictory results: Some found that maternal infection with influenza increased the risk of a child developing schizophrenia 20 years later, but others did not. Only in the last few years have scientists sorted it out. Instead of assuming that every child who had been in utero at the time of a flu outbreak had been infected, researchers began examining mothers’ blood for the telltale antibodies that indicate a past infection. With that advance, the link became clear: As researcher Alan Brown of Columbia University calculated in a 2010 paper, more than 30 percent of the risk of developing schizophrenia comes from prenatal exposure to the flu virus.

The flu virus is not the only culprit. In 2000, Brown and colleagues produced the first watertight evidence that young adults who had been exposed to the rubella virus (aka “German measles”) while they were fetuses less than three months old had a five-times-greater risk of developing psychosis—including schizophrenia—than their peers who had not been exposed to the virus.

Contrary to expectations, however, it is not rubella or other viruses, per se, that harm the developing brain. That became clear as scientists documented a veritable menagerie of maternal infections able to cause psychiatric and neurodevelopmental illnesses—not only flu and rubella but also toxoplasmosis and genitourinary infections. To their shock, scientists began to find that, although mothers had antibodies to flu in their blood (showing that the mother had been infected), the kids—in utero at the time—often did not: They were not infected with the virus.

Dr. Ian Lipkin
“It is the reaction of the mother’s immune system to the infection, not the infection itself, that affects the developing brain,” says Columbia University’s Dr. Ian Lipkin.

So what was happening? It’s not that the fetus becomes infected. Instead, the infection triggers the mother’s innate immune system, the army of molecules that prime other cells to kill the invaders. “It is the reaction of the mother’s immune system to the infection, not the infection itself, that affects the developing brain,” says Lipkin. Specifically, a flood of antibodies and other immune-system chemicals with names like chemokines and cytokines surges through the placenta and into the fetus. “The result may be compromised fetal brain development,” explains Dr. Robert Freedman, a psychiatrist at the University of Colorado Denver Health Sciences Center.

Researchers put the final piece into the puzzle when they exposed pregnant mice to a molecular mimic of viral RNA (viral genes are often made of RNA instead of the closely related DNA). That exposure put the brakes on special stem cells that give rise to new nerve cells (neurons)—not just in the embryo but on into adulthood. Most egregiously, it blocked the growth of a specialized kind of neuron destined for the neocortex, the most advanced region of the brain.

How bad was the damage? The offspring of the virus-exposed mice could not even walk normally, reported epidemiologist Mady Hornig of Columbia and colleagues last year. And, after the mice grew to adulthood, they had other neurological abnormalities as well.

Because the mother’s immune system’s response to infection causes the harm to the fetus, almost any virus is a potential threat to the developing fetus. “The damage to neurons and neural stem cells might not be evident right away,” says Hornig, “but manifests later as cognitive and behavioral problems.”

How bad will those problems become? “The specific result depends on the timing,” says Lipkin. He explains that if neural stem cells are killed by the flood of immune-system molecules (the chemokines and cytokines) before they mature, they will not take their rightful place in the brain’s neural networks. Circuits that are forming at the time of the infection will be most vulnerable, while those already hooked up are spared. In schizophrenia, for instance, there are abnormally low numbers of neurons and incomplete clustering in a particular area of the brain, hinting that something went wrong when these regions were being constructed. The effect of the viral infection may be delayed even into adulthood if a circuit damaged by the cytokine flood is not recruited until that time.

The apparent link between prenatal viral infection and later brain disorders led Johns Hopkins Children’s Hospital to establish in 1998 the nation’s first pediatric research center to investigate links between severe mental illness and prenatal or early childhood viral infections. Last year, Robert Yolken, who heads the Stanley Division of Developmental Neurovirology at Johns Hopkins Medical School, and colleagues reported that in their study of all children born in Denmark since 1981, mothers who had been infected with herpes simplex 2 had a 56 percent greater risk of having a child who later developed schizophrenia.

Dr. Robert Yolken
Dr. Robert Yolken of Johns Hopkins Children’s Center believes that better understanding the role infections play in developing schizophrenia may lead to more effective treatments in the future.

Although current thinking holds that the mother’s immune response, not the virus itself, is the culprit behind viral causes of mental illness and neurodevelopmental disorders, there may be exceptions. Yolken, for instance, suspects that herpes and influenza viruses (as well as the Toxoplasma gondii parasite carried by cats and other warm-blooded animals) might invade the brain and lie dormant for years before triggering schizophrenia or bipolar illness.

The evidence that viruses can cause psychiatric illnesses and neurodevelopmental disorders does not mean they are the only causes. For example, bacteria can also trigger an immune response, which may explain why strep infection can damage the developing brain, leading to the constellation of tics, obsessive-compulsive disorder, and other symptoms called Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal infections (PANDAS). Additionally, many mental illnesses are more likely to arise in people with a family history of them, indicating that they are at least partly heritable. But the failure of geneticists to find genes that have a strong effect on the likelihood of developing schizophrenia, depression, bipolar disorder, or autism suggests that genes do not cause these complex disorders the way a single gene directly causes, say, sickle-cell disease. More likely, says Lipkin, genes make people more or less susceptible to other causes of these diseases—including viruses.

Although the research is still new, scientists believe that it is not too early for obstetricians to take the emerging findings into account. The most obvious step is to monitor pregnant women closely for infections—even those that seem mild—because what may be a minor inconvenience to the mother could be devastating to the unborn child. Women should be educated to be aware of when they might have contracted a viral infection and to tell their obstetrician, who may need to treat them more aggressively than is current practice. In animal studies, after pregnant females were exposed to virus genes, the damage to their unborn pups was prevented when the mothers were given nonsteroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen. That provides a rationale for using these drugs when a pregnant woman contracts an infection, says Hornig. Currently, obstetricians prescribe acetaminophen (Tylenol) for pain relief in pregnant women, but that compound does not have the anti-inflammatory effects needed to turn off the cytokine flood.

The old expression “take two aspirin—or ibuprofen—and call me in the morning” never had so much meaning.

Nathan Wolfe
Nathan Wolfe’s research on viruses has earned him the nickname “the Indiana Jones of virus hunters.”

The next deadly scourge—and where it’s most likely to originate.

It is no coincidence that the most widespread and dangerous viruses began infecting humans some 11,000 years ago, says virologist Nathan Wolfe, CEO of Global Virus Forecasting (GVF) Initiative. When animals and people live in close proximity, as they began to do with the advent of agriculture and animal husbandry, viruses from the former can jump the species barrier—as did HIV/AIDS, Ebola, Marburg, and more kinds of flu than you can count.

Wolfe, who founded GVF in 2008 and has been nicknamed the “Indiana Jones of virus hunters,” warns that our fellow mammals aren’t done with this problematic sharing. Some 60 percent of emerging viruses—that is, those new to medical science—come from animals. And as the world becomes smaller and more connected, allowing a traveler to get from the deepest jungles of Africa to London or New York or Tokyo in less than a day, the chance of a virus jumping from a monkey to a bush meat hunter to a western tourist and the entire developed world has soared. In his upcoming book The Viral Storm: The Dawn of a New Pandemic Age (to be published in October), Wolfe argues that this has made us sitting ducks for another global epidemic.

The greatest threats come from two sources: completely new viruses (such as HIV/AIDS) and viruses that mutate. Primates are the most likely reservoirs of the former because the closer the evolutionary relationship, the more likely a virus is to cross over. (For example, there are no cases of viruses jumping to humans from fish or insects, says Wolfe.) But viruses from mammals other than primates can also spread through the human population like wildfire. The H1N1 virus from pigs was so highly transmissible that it went from infecting zero percent of the human population to 10 percent in only a year, notes Wolfe, killing some 20,000 to 30,000 people. The only reason its toll has not been greater is that transmissibility and lethality are inversely related; that’s why Ebola, though deadly, is not highly transmissible.

An even greater threat is mutation of existing human viruses. If one that is deadly but not very transmissible or very transmissible but not deadly acquires genes for that second trait, the results could be catastrophic. That is most likely to happen when viruses from widely separated regions come into contact—as is more and more likely in what Wolfe calls “this viral mixing vessel” caused by global travel.

“Viruses aren’t static,” he says. “They change over time; they exchange genes with other viruses, which can make them more likely to develop deadly recombinants. The greatest threat is probably something we don’t even know is out there.”