by Janet A. Ginsburg

"The biggest breakthrough in the history of psychiatry was recognizing that syphilis causes insanity and that it could be prevented with antibiotics," says evolutionary biologist Paul Ewald.  But after the discovery nearly a century ago that an antibiotic (Salvarsan) could reduce schizophrenic symptoms in syphilis patients, interest in infectious disease as a cause of mental illness all but evaporated. The studies of Mind (psychiatry) and Brain (neurology) went their separate ways.  Remnants of that schism remain today: Once a physical cause is found for psychiatric symptoms, a patient is no longer classified as having a mental illness.

Some of these infectious agents have been linked to the same disorders (e.g., influenza and toxoplasma gondii to schizophrenia), which is not as surprising at it sounds: Psychiatric conditions such as schizophrenia, bipolar disorder and autism are diagnosed based on suites of behaviors. That points to the importance of “the final common pathway.” Whether someone suffers a blow to the head, is exposed to harmful chemicals,  has a haywire gene, a bout with an infection -- or a combination of any of the above -- the resulting behavioral problems may be identical, caused by the destruction of the same neurological pathways.

Infectious disease alone cannot account for every case of mental illness.  But its role is likely far more significant that has been traditionally noted.  Here are a half dozen prime suspects:

LYME DISEASE

During the 1970s, several children living near Lyme, Connecticut were diagnosed with what appeared to be arthritis. Such severe joint pain in the young was unusual, and a cluster of cases raised flags.

Lyme Disease (LD), as it came to be known, is not a new scourge on the block, just a newly identified one. Reports of symptoms matching early stages of the illness – a distinctive bull’s eye skin rash, fatigue and joint pain –were first described in Europe over a century ago. By the 1940s, spirochetes, which researchers suspected were carried by ticks, had been isolated from the rash. But the prevailing wisdom was that spirochetes were found exclusively for soft-shelled ticks, so for decades scientists looked in the wrong ticks. Another 40 years would pass until Willy Burgdorfer, a medical entomologist studying Rocky Mountain spotted fever, accidentally discovered the bacteria in hard-shelled deer ticks. “It was serendipity that I knew what I was looking at,” he recalls.

Like its distant cousin syphilis -- also caused by a spirochete -- Borrelia burgdorferi, the LD spirochete, burrows into body tissues, including brain tissue where it can cause all sorts of neuropsychiatric mayhem. It can also lie dormant for months or even years, making “late stage Lyme” very difficult to diagnose. The standard blood antibody test is prone to “false negatives,” especially if spirochetes are buried in tissue or circulating as cysts in cerebrospinal fluid. Although a short course of antibiotics can stem an infection caught early, catching it early isn’t always so easy. According to some estimates, the bull’s eye rash only appears in half the cases; and many victims don’t remember being bitten by a tick.

Using brain scans, Columbia University neuropsychiatrist Brian Fallon discovered that patients with chronic LD have significant reduction in blood flow in brain regions associated with memory and visual-spatial organization. There are many cases of patients ultimately diagnosed with LD of first being diagnosed with depression, bipolar disease and even schizophrenia.

In another small, but particularly disturbing study, Fallon also looked at children, who are especially at risk because they play outside where the ticks are. Compared to the healthy kids in the control cohort, all the LD children – who were diagnosed on average a year after infection – showed significant cognitive and psychiatric problems. They scored low on tests for memory and perception. They were depressed—some with thoughts of suicide. And because their symptoms matched descriptions of psychiatric disorders, including Attention Deficit Disorder (ADD), many of the kids were given psychotropic drugs. While the drugs often helped alleviate some of the symptoms, they did not target the underlying infection. None of the kids completely recovered. 

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Incidence records for LD are spotty because most cases aren’t reported, but it is widely believed to be the most prevalent vector-borne illness in the U.S., with tens (some think hundreds) of thousands of new cases each year.

Borrelia burgdorferi is actually part of a large group of related bacteria found all over the world, in all sorts of ticks, all causing similar disease, though of varying severity. In 1996, a new spirochete, B. lonestari, discovered in the lonestar tick common throughout the southern tier of the United States, was linked to Lyme symptoms. As yet, there are no tests, so no case statistics; and the very real possibility of patients being diagnosed and treated for psychiatric conditions while their infections go undetected.

TOXOPLASMOSIS

Toxoplasma gondii (toxo), a protozoan parasite, is a ubiquitous pathogen that infects everything from cats and cattle, to sea otters and people. Worldwide, human infection rates range from 15% in the U.S. (45 million people), to over 60% elsewhere. Hundreds of millions of people have it, usually infected either by contact with cat feces or from eating undercooked meat or poultry. Although infection is common, schizophrenics are two to three times as likely to be infected as non-schizophrenics.

Generally, toxo causes no more than a mild flu-like illness and is often misdiagnosed as passing viral infection. But like Borrelia spirochetes, the parasites can burrow into tissue and lie dormant as cysts for long as a host’s lifetime. Still, even a dormant parasite, if lodged in critical brain tissue, can muck up the works. People with latent cases of toxo have slightly slower reaction times and reduced attention spans, which researchers at Charles University in Prague have linked to an increased risk for auto accidents.

In the pantheon of mild-altering microbes, toxo is unique in its mission and methods: The parasite must get itself into a cat, its primary host, in order to reproduce, which means its intermediate host, normally a rodent, must be eaten. In a series of experiments, Joanne Webster at the University  of Oxford, discovered that toxo-addled wild rats not only lost their natural fear of wandering into open spaces, they were actually attracted to cat smells, essentially delivering themselves for dinner.

Intriguingly, an impaired sense of smell may also turn out to be a good predictor for which high-risk human patients develop full-blown schizophenia -- although so far there has no research into a toxoplasma link.

Fortunately, infected humans don't end up as cat food, but acute toxo can cause hallucinations and other psychotic behaviors. In fact, both rats and people may be tripping: studies from the 1950s and 60s suggest that toxo can trigger the production of LSD-like substances in the brain.

The route of infection may determine the risk for psychosis, says Paul Ewald who studies the evolution of infectious diseases. Acquiring the parasite through food mimics the role of the primary host, the cat,  which doesn’t get sick. But infection through exposure to cat feces puts a person in the far more dicey rodent role.

A developing fetus can also acquire toxo through maternal infection. Psychiatric epidemiologists Ezra Susser and Alan Brown have found a correlation between high maternal levels of anti-toxo antibodies and schizophrenia in their children. A pre-natal, or even an infection shortly after birth, can impact neurodevelopment, with catastrophic results that appear decades later.

On a more hopeful note, parasitologist Joanne Webster has discovered that anti-toxo and anti-psychotic drugs were both effective at preventing aberrant behaviors in rats. This suggests that disrupting any part of the disease pathway, whether at the source or further down the line, provides a promising option for treatment. 

INFLUENZA

To the list of maladies caused by the flu – headache, fever, fatigue, coughing, sore throat, runny nose, body aches, and an upset stomach, add schizophrenia…

That’s not to say it’s a huge risk: Most pregnant women who get flu don’t have schizophrenic offspring; and exposure doesn’t guarantee a schizophrenic child. But the increased risk is certainly enough to raise a flag and may, according to Brown, account for as many as 14% of all schizophrenia cases --  if the results hold up and can be duplicated.

To reach their findings, Susser and Brown sifted through the medical records of 20,000 women who were pregnant in Alameda county, California, between 1959 and 1966. The mothers -- all patients at Kaiser-Permanente, the largest healthcare provider in the region -- were part of a massive child health and development study. The real stroke of epidemiological luck, however, was that most of their children are still in the Kaiser-Permanente system. Since symptoms of schizophrenia typically don’t appear until the teen years or twenties, being able to access decades-worth of data was key.

First, the team had to determine which children had been diagnosed with schizophrenia spectrum disorders. Next, the corresponding maternal blood samples, which had been carefully stored, were tested for antibodies to the particular strains of influenza virus circulating when the mothers were pregnant. Finally, the results were compared with blood tests from a matched control set of mothers of mentally healthy children from the same Kaiser-Permanente group.

Exactly how the virus causes schizophrenia is still unclear. According to Paul Patterson at the California Institute of Technology in Pasadena, the virus may not be doing the damage directly. He injected pregnant mice with a “molecular mimic” of the flu virus, which generates an immune response without causing infection. Nevertheless, offspring mice developed behavioral abnormalities reminiscent of schizophrenia, suggesting that the stress of a maternal immune response alone may be enough to affect neurodevelopment (also, a link to another study). That raises a very thorny question about whether mothers-to-be should -- or shouldn’t -- receive flu shots.