The old theory that schizophrenia, a devastating mental illness, might be triggered by a virus or other infectious agent that deranges normal brain development is gaining new ground, researchers reported here last week.
That proposition is far from proven, and even its proponents say that several factors--including an inherited susceptibility--probably combine to produce the disorder. But there is increasing evidence to suggest that genes from viruses that were long ago incorporated into the human genome may be involved in schizophrenia.
One new line of investigation suggests that these quiescent viral genes, which originally came from retroviruses (a large family that includes the human immunodeficiency virus or HIV, the cause of AIDS), can sometimes be activated when a person is infected with a different virus, or by some other factor during fetal life or infancy. This, in turn, may cause altered brain development, leading to the disease.
According to this theory, "there are other viruses, common in the environment, that are turning on [these retrovirus genes] in some people during brain development," said Robert H. Yolken, director of the Stanley Division of Developmental Neurovirology at Johns Hopkins University in Baltimore.
The idea that mental illnesses such as schizophrenia might be triggered by infections dates back to the mid-19th century. However, researchers said the viral theory has received greater credibility in the past few years, particularly as genetic studies have failed to find conclusive evidence for a "schizophrenia gene."
"I would think that the research community in general considers [the theory of viral triggers for schizophrenia] one of the significant leads that we have," said David Shore, associate director for clinical research at the National Institute of Mental Health. "I would say it's pretty unlikely that it is a particular virus. It may well be that it's either the effect of a nonspecific infection or perhaps the body's reaction to fighting it."
Schizophrenia affects 2.3 million Americans and typically produces its first symptoms between the ages of 16 and 25. People with the illness often hear voices, suffer from delusions, have abnormal thought processes and may experience extremes of mood.
In recent years, detailed studies comparing the brains of schizophrenics with those of people without the disease have revealed subtle differences in various parts of the brain, including the hippocampus, amygdala, thalamus, cingulate gyrus and prefrontal cortex. These areas of the brain are major relay stations filtering all sensory input from the outside world. But why they apparently develop abnormally in schizophrenics is a mystery.
Researchers have suspected viral infections might contribute to schizophrenia and to bipolar disorder, another serious mental illness, because more than 200 studies have found that people born between December and March have rates of these disorders that are 5 to 8 percent higher than people born at other times of year, said E. Fuller Torrey, co-director of the Stanley Laboratory on Brain Research at the Uniformed Services University of the Health Sciences in Bethesda. Viral infections are more frequent during the winter months. Some studies have also found slightly higher rates of schizophrenia in the children of women who were pregnant during major epidemics of influenza.
Torrey said eight or nine studies in various countries have also found that schizophrenia rates among people born or raised in cities are about twice as high as among people who are born or grow up in rural areas, suggesting environmental factors could be involved.
Bipolar disorder (also known as manic depression) appears to have a stronger genetic component than schizophrenia. For example, in pairs of identical twins, if one twin has bipolar disorder, the chance of the other twin having it is between 55 and 65 percent, Torrey said. If one of a pair of such twins has schizophrenia, the likelihood of the other twin having it is only 30 to 35 percent.
Last week, researchers presented new findings on the possible role of viruses in schizophrenia at a Bethesda symposium sponsored by Johns Hopkins University School of Medicine.
One study used a trove of frozen blood samples that were collected from 53,000 pregnant women at hospitals around the country in the 1950s and 1960s. Among infants born to women in the study who lived in Boston and Providence, R.I., 27 were identified as having developed schizophrenia, bipolar disorder or psychosis, a related form of mental illness. Stephen Buka of the Harvard School of Public Health tested the blood obtained from these patients' mothers during their pregnancies.
Compared with blood from mothers of unaffected children in the study, samples from the mothers of the affected children had significantly higher levels of antibodies (indicative of infections during pregnancy) and, in particular, higher levels of antibody to the type 2 herpes virus, a sexually transmitted infection that sometimes causes severe brain damage in newborn infants. Buka said this is not yet sufficient to prove that the herpes virus contributes to development of schizophrenia, but he intends to conduct further studies.
"Retroviruses have moved to center stage" in the past two years as possible triggers of schizophrenia, said Hopkins's Yolken. In animals and people, such viruses can cause infections that may remain latent for long periods but may eventually produce abnormal brain function and behavior. HIV, for example, causes dementia in some patients and sometimes produces symptoms resembling schizophrenia.
Results from several studies presented at the conference suggest that so-called endogenous retroviruses--viral genes that have become incorporated as part of human chromosomes and are passed from parent to child--may play a role in schizophrenia. Yolken suggested that other viral infections, hormones or chemical messengers released by the immune system might activate such genes, setting off the process that leads to development of the disorder.
Genes that originally came from retroviruses are apparently present in all animals, and make up about 1 percent of the human genome, said Jonas Blomberg of Sweden's University of Uppsala Department of Microbiology. Some of these genes make proteins that can be detected in many human organs, and in a few tissues--especially the placenta and certain cancers--the genes can code for the manufacture of complete, infectious virus particles.
Hakan Karlsson of Stockholm's Karolinska Institute looked for endogenous retroviruses in spinal fluid samples from 35 patients who had just begun to suffer symptoms of schizophrenia. Spinal fluid surrounds the brain and spinal cord and is often used to test for brain infections. The samples were obtained within 14 days of admission to the hospital. He detected genetic material from such viruses in 10 patients (29 percent). The rate was lower (8 percent) in a group of schizophrenics who had been sick for an average of four years and lower still (5 percent) in a third group whose symptoms had begun an average of 14 years earlier.
There was no sign of such viruses in spinal fluid samples taken from healthy people or from a group of non-schizophrenic patients undergoing spinal taps for a different reason.
The viral genes found in the schizophrenic patients appeared to be related to a retrovirus called MSRV (multiple sclerosis-related virus) that was recently discovered in patients with that degenerative neurological disease. Researchers are doing further studies trying to determine whether genes from such viruses produce proteins that damage cells or whether they can manufacture complete viral particles.
"The ultimate goal is to determine whether the virus has anything to do with the disease," said Lorraine Jones-Brando of the Stanley Division of Developmental Neurobiology at Hopkins.
If retroviruses contribute to schizophrenia, it's possible that some of the drugs developed to treat AIDS--a retrovirus infection--might help people with the mental disorder, Torrey suggested. He said he has proposed a study using one of the newer anti--HIV drugs (he declined to say which one) as an experimental treatment for people with schizophrenia and bipolar disorder. The drug's manufacturer and various regulatory committees are considering the proposal.
"We have enough evidence that this is not just a shot in the dark," he said.